SOX9 reprograms endothelial cells by altering the chromatin landscape
Open accessAbstract
The transcription factor SOX9 is activated at the onset of endothelial-to-mesenchymal transition (EndMT) during embryonic development and in pathological conditions. Its roles in regulating these processes, however, are not clear. Using human umbilical vein endothelial cells (HUVECs) as an EndMT model, we show that SOX9 expression alone is sufficient to activate mesenchymal genes and steer endothelial cells towards a mesenchymal fate. By genome-wide mapping of the chromatin landscape, we show that SOX9 displays features of a pioneer transcription factor, such as opening of chromatin and leading to deposition of active histone modifications at silent chromatin regions, guided by SOX dimer motifs and H2A.Z enrichment. We further observe highly transient and dynamic SOX9 binding, possibly promoted through its eviction by histone phosphorylation. However, while SOX9 binding is dynamic, changes in the chromatin landscape and cell fate induced by SOX9 are persistent. Finally, our analysis of single-cell chromatin accessibility indicates that SOX9 opens chromatin to drive EndMT in atherosclerotic lesions in vivo. This study provides new insight into key molecular functions of SOX9 and mechanisms of EndMT and highlights the crucial developmental role of SOX9 and relevance to human disease.
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Written from the paper’s full text.
TL;DR
SOX9 expression in human endothelial cells is sufficient to drive endothelial-to-mesenchymal transition and displays pioneer-factor-like activity by opening silent chromatin. Genome-wide profiling links SOX9 chromatin opening to SOX dimer motifs and H2A.Z, while dynamic SOX9 binding is associated with H3S28 phosphorylation and persistent changes in chromatin and cell fate.
Key findings
- Ectopic SOX9 in HUVECs induced mesenchymal morphology, increased migration, downregulated endothelial markers CD31 and ERG, and upregulated POSTN and VIM; RNA-seq found 2587 upregulated and 2219 downregulated genes, enriched for EMT and mesenchymal signatures.
- SOX9 caused a major chromatin-state switch: 50 607 regions changed state, including 6298 previously primed, quiescent, or repressed regions that became activated and 9118 active regions that changed state; promoters were less dynamic than distal elements.
- CUT&RUN identified 3473 SOX9-bound regions, mostly distal (49%) or within gene bodies (45%), with only about 6% at TSS/proximal promoters; 543 direct targets (63%) were upregulated and 324 (37%) downregulated. Binding modes were C1 12%, C2 10%, C3 23%, and C4 >50%; C2 regions were closed before SOX9 and gained accessibility and active marks, with enrichment of SOX dimer motifs and H2A.Z.
- SOX9 binding was highly dynamic: at 4 days only 6% of regions with increased accessibility had detectable SOX9 binding, but earlier timepoints accounted for 67% of those regions (3548 regions plus 336 C2 regions); H3S28P abolished SOX9 binding in peptide arrays and PLA, and scATAC-seq in atherosclerotic lesions showed SOX motifs enriched in newly accessible EC8 regions.
Methods
- HUVECs were transduced with SOX9 or empty vector; assays included RNA-seq, CUT&RUN, CUT&Tag for H3K4me1/H3K27ac/H3K27me3/H3S28P, ATAC-seq at 24/48/72/96 h, migration assays, immunostaining, peptide arrays, and proximity ligation assays; mouse embryonic hearts were examined at E9.5–E12.5.
- Published mouse atherosclerosis scRNA-seq and scATAC-seq datasets were reanalyzed, integrated, clustered, and assessed for pseudotime progression and motif enrichment.
- Main analyses included differential expression, GSEA, chromatin-state classification, MACS2 peak calling, HOMER motif search, EChO fragment-size analysis, GREAT gene association, and ChAsE clustering.
Limitations
- Stated: whether SOX9 requires destabilized nucleosomes or H2A.Z for chromatin opening remains undetermined; SOX9’s chromatin role may differ by cell type, as noted for chondrogenesis and gonadal cell fate transition; not all H2A.Z- and SOX-motif-containing sites were bound; the largest C4 cluster likely represents non-specific binding or scanning and lacked enriched biological processes.
- Evident: the HUVEC overexpression model lacks endogenous SOX9, so SOX9 levels and context may not fully reflect in vivo EndMT; the atherosclerosis evidence is based on reanalysis of single-cell datasets and is correlative, without direct SOX9 loss-of-function in lesions.
- Evident: CUT&RUN included two biological replicates at 96 h and one replicate for the SOX9 time course, which may limit inference about dynamic binding.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
44 of 60 cited sources checked · 26 supported · 2 flagged · accuracy not yet measured
- Premisecitation
The identified SOX motifs are similar to previously identified motifs for SOX9.
“which are similar to previously identified motifs for SOX9 (5,17,53,62).”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [5] Huang, 2015, SOXE transcription factors form selective dimers on non-compact DNA motifs through multifaceted interactions between dimerization and high-mobility group domains, Sci. Rep. source
- cites [17] Garside, 2015, SOX9 modulates the expression of key transcription factors required for heart valve development, Development source
- cites [53] Oh, 2014, SOX9 regulates multiple genes in chondrocytes, including genes encoding ECM proteins, ECM modification enzymes, receptors, and transporters, PLoS One source
- cites [62] Ohba, 2015, Distinct transcriptional programs underlie sox9 regulation of the mammalian chondrocyte, Cell Rep. source
- Interpretationown data
No significant biological processes were associated with C4 regions, suggesting C4 represents non-specific binding or scanning by SOX9.
“we did not identify significant biological processes associated with the regions in C4, although this was the largest of the four clusters, suggesting that this cluster represents non-specific binding or scanning by SOX9 (63).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [63] Zaret, 2016, Chromatin scanning by dynamic binding of pioneer factors, Mol. Cell source
In the passage labeled Abstract (page unavailable), the paper links nonspecific FoxA1 binding to its potential to scan closed chromatin. It does not examine SOX9 or C4 regions, so it supports the proposed scanning mechanism only by analogy, not its application to C4. The absence of significant biological processes is presented as the citing authors’ own finding. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Disturbing SOX9 dimerization abolishes its ability to remodel chromatin in vitro.
“previous study showing that disturbing SOX9 dimerization abolish its ability to remodel chromatin in vitro (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
- Interpretationown data
SOX9 must dimerize to open chromatin.
“Our results strongly suggests that SOX9 must dimerize to open chromatin in agreement with the previous study showing that disturbing SOX9 dimerization abolish its ability to remodel chromatin in vitro (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
- Interpretationcitation
SOX9 acts as a master regulator.
“highlighting the role of SOX9 as a master regulator (17,54,55).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [17] Garside, 2015, SOX9 modulates the expression of key transcription factors required for heart valve development, Development source
- cites [54] Akiyama, 2002, The transcription factor sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of sox5 and sox6, Genes Dev. source
- cites [55] Hino, 2014, Master regulator for chondrogenesis, sox9, regulates transcriptional activation of the endoplasmic reticulum stress transducer BBF2H7/CREB3L2 in chondrocytes, J. Biol. Chem. source
- Findingcitation
Among upregulated genes were previously characterized SOX9 target genes, such as ECM genes encoding collagens IX and XI, as well as TF genes SOX5, SOX6, CREB3L2, and NFIA.
“Among the upregulated genes were previously characterized SOX9 target genes, such as ECM genes encoding collagens IX and XI (53), as well as other TF genes like SOX5, SOX6, CREB3L2, and NFIA”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [53] Oh, 2014, SOX9 regulates multiple genes in chondrocytes, including genes encoding ECM proteins, ECM modification enzymes, receptors, and transporters, PLoS One source
- Interpretationreasoning
H3S28P may evict SOX9 from nucleosomes following chromatin opening and activation.
“This suggests that H3S28P, which is associated with open chromatin and activation of transcription (65), may evict SOX9 from nucleosomes following chromatin opening and activation.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [65] Josefowicz, 2016, Chromatin kinases act on transcription factors and histone tails in regulation of inducible transcription, Mol. Cell source
- Premisecitation
SOX9 chromatin remodeling of nucleosomes assembled in vitro was abolished when SOX9 dimerization was disrupted.
“supporting a study showing that SOX9 chromatin remodeling of nucleosomes assembled in vitro was abolished when SOX9 dimerization was disrupted (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
- Findingown data
When SOX9 is acting as a pioneer TF, the optimal pioneering motif is a slightly degenerate dimer motif.
“According to our data, when SOX9 is acting as a pioneer TF, the optimal pioneering motif is a slightly degenerate dimer motif, supporting a study showing that SOX9 chromatin remodeling of nucleosomes assembled in vitro was abolished when SOX9 dimerization was disrupted (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
- Interpretationown data
SOX9 harbours the pioneer TF ability to engage target sites in closed chromatin.
“Our results suggests that SOX9 harbours this ability but, as observed with other pioneer TFs (47,69,70), not all SOX9 binding events result in opening of chromatin.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [47] Mayran, 2018, Pioneer factor pax7 deploys a stable enhancer repertoire for specification of cell fate, Nat. Genet. source
- cites [69] Takaku, 2016, GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler, Genome Biol. source
- cites [70] Fuglerud, 2017, A c-Myb mutant causes deregulated differentiation due to impaired histone binding and abrogated pioneer factor function, Nucleic Acids Res. source
The Introduction defines pioneer transcription factors as able to associate with closed chromatin, and the Discussion presents evidence of pioneer activity for c-Myb. Neither passage establishes that SOX9 has this ability; the citing sentence presents that as the citing authors’ own result, not a finding of this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
SOX9 chromatin binding was unaffected by disrupted dimerization.
“Interestingly, the same study also showed that SOX9 chromatin binding was unaffected by disrupted dimerization, which is in line with our observation that the monomer motif was more enriched in regions where SOX9 bound but did not open chromatin.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
The Results section, “Binding of recombinant full-length and mutant SOX9 to the Col2a1 enhancer” (page unavailable), reports that the dimerization mutant still bound an isolated DNA probe and had similar binding kinetics to wild-type SOX9. The Discussion specifies that this stable binding was to naked DNA; the paper does not establish that binding to chromatin was unaffected. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
Downregulated genes by SOX9 included endothelial markers VWF, CDH5, PECAM1 and endothelial-associated TFs SOX7, SOX18, ERG, LMO2.
“Downregulated genes included endothelial markers like von Willebrand factor (VWF), VE-cadherin (CDH5), and CD31 (PECAM1), as well as some key endothelial-associated TFs, such as SOX7, SOX18, ERG and LMO2 (Figure 2B, right panel).”
Quote in the paperSubstantial claim - Findingown data
Downregulated genes were enriched for inflammatory signaling pathways and endothelial cell type signature gene sets.
“Downregulated genes were enriched for inflammatory signaling pathways and cell type signature gene sets of endothelial cells.”
Quote in the paperSubstantial claim - Findingown data
SOX9-induced mesenchymal morphology in HUVECs was permanent and robust, as cells could be passaged without reverting.
“Notably, the cells could be passaged without reverting to their original morphology, suggesting the mesenchymal morphology induced by SOX9 was permanent and robust.”
Quote in the paperSubstantial claim - Findingown data
SOX9 expression downregulated some genes encoding transcription factors known to have a role in EMT, such as SNAI1 and ZEB1.
“we observed a downregulation of some genes encoding TFs known to have a role in EMT, like SNAI1 and ZEB1”
Quote in the paperSubstantial claim - Findingown data
Among the most upregulated genes by SOX9 were ECM components including collagens and mesenchymal markers POSTN, CDH2, CDH11.
“Among the most upregulated genes were components of ECM, including collagens, as well as mesenchymal markers like Periostin (POSTN), N-cadherin (CDH2) and Cadherin-11 (CDH11).”
Quote in the paperSubstantial claim - Findingown data
Mesenchymal markers MMP2, TGFBI and VCAN were expressed significantly higher in endothelial clusters containing SOX9-expressing cells compared to other endothelial clusters.
“Furthermore, the mesenchymal markers MMP2, TGFBI and VCAN, were also expressed significantly higher in the endothelial clusters containing SOX9-expressing cells compared to the other endothelial clusters (Supplementary Figure S2A).”
Quote in the paperSubstantial claim - Findingown data
By six days post-transduction, SOX9-expressing HUVECs changed morphology from cobblestone-like endothelial shape to elongated spindle-shape characteristic of mesenchymal cells.
“By six days post-transduction the cellular morphology changed from the cobblestone-like shape of endothelial cells to an elongated spindle-shape characteristic of mesenchymal cells (Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
In both scRNA-seq datasets, one large endothelial cell cluster almost exclusively consisted of cells from atherosclerotic lesions (EC8 in Andueza et al. and EC6 in Chen et al.).
“Interestingly, one large endothelial cell cluster in both datasets almost exclusively consisted of cells from atherosclerotic lesions, EC8 and EC6, from Andueza et al. and Chen et al., respectively.”
Quote in the paperSubstantial claim - Findingown data
SOX9 expression is induced in endothelial cells during EndMT in vivo.
“SOX9 expression is induced in endothelial cells during EndMT in vivo”
Quote in the paperSubstantial claim - Findingown data
By E12.5, there is further expansion of the mesenchyme consisting of SOX9-expressing cells.
“By E12.5, we observed a further expansion of the mesenchyme consisting of SOX9-expressing cells (Supplementary Figure S1A).”
Quote in the paperNot a substantial claim - Findingown data
RNA-seq in HUVECs four days after SOX9 transduction identified 2587 upregulated and 2219 downregulated genes (log2 ratio >0.5 or <-0.5, P<0.05).
“2587 genes were upregulated and 2219 genes were downregulated with SOX9 expression (log2 ratio > 0.5 or ←0.5, P-value < 0.05) (Figure 2A, B and Supplementary Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
In HUVECs, SOX9 primarily binds distal regulatory elements inside or outside gene bodies.
“indicating that in HUVECs, SOX9 primarily binds distal regulatory elements inside or outside gene bodies.”
Quote in the paperNot a substantial claim - Findingown data
We identified 3473 SOX9 bound regions in HUVECs four days after transduction.
“We identified 3473 SOX9 bound regions (Supplementary Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
SOX9 binds to active and open chromatin regions as well as to closed and silent chromatin.
“our profiling of the chromatin landscape shows that SOX9 binds to active and open chromatin regions as well as to closed and silent chromatin.”
Quote in the paperSubstantial claim - Findingown data
9118 regions that were active in endothelial cells changed state with SOX9 expression.
“whereas 9118 regions that were active in endothelial cells changed state.”
Quote in the paperSubstantial claim - Findingown data
6298 regions that were primed, quiescent, or repressed in endothelial cells prior to SOX9 expression were activated with SOX9 expression.
“6298 regions that were primed, quiescent, or repressed in endothelial cells prior to SOX9 expression, were activated with SOX9 expression”
Quote in the paperSubstantial claim - Findingown data
Chromatin changes induced by SOX9 in C1 and C2 regions lead to an overall upregulation of the associated genes.
“Chromatin changes induced by SOX9 in C1 and C2 regions lead to an overall upregulation of the associated genes”
Quote in the paperSubstantial claim - Findingown data
Regions that lost active histone marks were linked with endothelial functions.
“whereas the regions that lost active histone marks were linked with endothelial functions (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
C1 had a larger proportion of sites in promoters and/or near the TSS of genes compared to the other clusters.
“C1 had a larger proportion of sites in promoters and/or near the TSS of genes compared to the other clusters”
Quote in the paperNot a substantial claim - Findingown data
SOX dimer motifs were enriched in <100 bp foci but not in >120 bp foci.
“found the SOX dimer motifs enriched in <100 bp foci but not in the > 120 bp foci”
Quote in the paperSubstantial claim - Findingown data
Other SOXE factors SOX8 and SOX10, which can bind the SOX9 dimer motif, were not expressed in HUVECs in either condition.
“other SOXE factors, SOX8 and SOX10, which can bind the SOX9 dimer motif, were not expressed in HUVECs in either condition (not shown).”
Quote in the paperSubstantial claim - Findingown data
Genes associated with activated distal elements were enriched for GO terms for mesenchymal functions.
“The genes associated with activated distal elements were enriched for GO terms for mesenchymal functions”
Quote in the paperSubstantial claim - Findingown data
SOX9 expression caused a major switch in chromatin states of distal elements, with 50607 regions changing chromatin state.
“SOX9 expression caused a major switch in chromatin states of distal elements; in total 50607 regions changed chromatin state (Figure 3A and B).”
Quote in the paperSubstantial claim - Findingown data
Genes downregulated by SOX9 expression in HUVECs were enriched in endothelial cells versus fibroblasts in atherosclerotic lesions.
“genes downregulated by SOX9 expression in HUVECs were enriched in endothelial cells versus fibroblasts in atherosclerotic lesions”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq data from atherosclerotic lesions accurately distinguish fibroblasts from endothelial cells.
- Findingown data
Chromatin opening predominantly occurred in regions containing the defined dimer motif and to a slightly lesser degree the degenerate dimer motif.
“Strikingly, chromatin opening predominantly occurred in regions containing the defined dimer motif and to a slightly lesser degree the degenerate dimer motif.”
Quote in the paperSubstantial claim - Findingown data
Other upregulated target genes include the Homeobox TF genes PRRX1 and PKNOX2.
“Other upregulated target genes include the Homeobox TF genes PRRX1 and PKNOX2”
Quote in the paperNot a substantial claim - Findingown data
Genes upregulated by SOX9 expression in HUVECs overlapped with genes upregulated in fibroblasts versus endothelial cells in atherosclerotic lesions.
“Genes upregulated by SOX9 expression in HUVECs overlapped with genes upregulated in fibroblasts versus endothelial cells in atherosclerotic lesions”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq data from atherosclerotic lesions accurately distinguish fibroblasts from endothelial cells.
- Findingown data
After subtraction of detected SOX9 bound regions, SOX dimer motifs were the most significantly enriched in newly opened chromatin.
“after subtraction of detected SOX9 bound regions, SOX dimer motifs were nonetheless the most significantly enriched in the newly opened chromatin”
Quote in the paperSubstantial claim - Findingown data
Expression of genes associated with C3 regions did not significantly change.
“Expression of genes associated with C3 regions did not significantly change.”
Quote in the paperNot a substantial claim - Findingown data
Promoters did not show the same level of histone modification dynamics as distal elements after SOX9 expression.
“Promoters did not show the same level of histone modification dynamics (Figure 3A, left panel).”
Quote in the paperSubstantial claim - Findingown data
Regions with decreased chromatin accessibility were enriched for motifs for AP-1 family TFs such as JUN and FOS, as well as motifs for endothelial TFs ETS and ERG.
“Regions with decreased chromatin accessibility were enriched for motifs for AP-1 family of TFs, such as JUN and FOS, as well as motifs for the endothelial TFs ETS and ERG”
Quote in the paperSubstantial claim - Findingown data
After removing expressed genes overlapping with C1 and/or C2 from C4 genes, there was no significant change in expression of the remaining C4 genes.
“After removing all expressed genes that overlap with C1 and/or C2 genes from C4 genes (18%), there was no significant change in expression of the remaining C4 genes”
Quote in the paperSubstantial claim - Findingown data
At PRRX1 and TGFBI loci, regions gained chromatin accessibility and active histone modifications with SOX9 expression.
“As shown at the PRRX1 and TGFBI loci, these regions gained chromatin accessibility and active histone modifications with SOX9 expression.”
Quote in the paperSubstantial claim - Findingown data
Four days after transduction, SOX9 binding was detected at only 6% of total regions with increased chromatin accessibility.
“Four days after transduction, we only detected SOX9 binding at 6% of the total regions with increased chromatin accessibility”
Quote in the paperSubstantial claim - Findingown data
When examining all H2A.Z peaks in closed chromatin in HUVECs, increased chromatin opening with SOX9 expression was observed in regions that also contained a SOX dimer motif.
“when we examined all H2A.Z peaks in closed chromatin in HUVECs, we observed increased chromatin opening with SOX9 expression in the regions that also contained a SOX dimer motif”
Quote in the paperSubstantial claim - Findingown data
SNAI2 was not expressed in our dataset.
“Another factor promoting EMT, SNAI2, was not expressed in our dataset.”
Quote in the paperSubstantial claim - Findingnone given
Mmp2, Tgfbi and Postn were direct target genes of SOX9 in HUVECs.
“which were direct target genes of SOX9 in HUVECs.”
Quote in the paperNot a substantial claim - Findingcitation
Not all SOX9 binding events result in opening of chromatin.
“Our results suggests that SOX9 harbours this ability but, as observed with other pioneer TFs (47,69,70), not all SOX9 binding events result in opening of chromatin.”
Quote in the paperSubstantial claim - Findingown data
SOX motifs were significantly less enriched in promoter regions of genes compared to distal chromatin regions in our data.
“Of note, we observed significantly lower enrichment of SOX motifs in promoter regions of genes compared to distal chromatin regions in our data (Supplementary Figure S7C).”
Quote in the paperNot a substantial claim - Findingown data
Mapping of SOX9 binding and the chromatin landscape identified different modes of SOX9 binding.
“Mapping of SOX9 binding and the chromatin landscape identified different modes of SOX9 binding.”
Quote in the paperSubstantial claim - Findingown data
H2A.Z was enriched in most sites with increased chromatin accessibility.
“we observed H2A.Z enriched in most sites with increased chromatin accessibility”
Quote in the paperSubstantial claim - Findingown data
The de novo motif retrieved for SOX9 was similar to the defined dimer motif but slightly more degenerate.
“The resulting motif was similar to the defined dimer motif, but slightly more degenerate.”
Quote in the paperNot a substantial claim - Findingown data
SOX9 binding at the tested timepoints accounted for 67% of opened regions where SOX9 binding was not detected at 96 h.
“SOX9 binding at the tested timepoints accounted for 67% of the opened regions where we did not detect SOX9 binding in our previous CUT&RUN (96 h post-transduction).”
Quote in the paperSubstantial claim - Findingown data
Some opened regions containing SOX motifs included the promoters and putative enhancers upstream of Mmp2, Tgfbi and Postn.
“Some of these opened regions containing SOX motifs included the promoters and putative enhancers upstream of Mmp2, Tgfbi and Postn (Figure 8D), which were direct target genes of SOX9 in HUVECs.”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
- Findingown data
By 48 h, SOX9 binding was detected in many newly opened regions where SOX9 was not detected at 96 h.
“by 48 h we detected SOX9 binding in many newly opened regions where we did not detect SOX9 bound at 96 h”
Quote in the paperSubstantial claim - Findingown data
H3S28P enrichment was increased in sites with chromatin opening upon SOX9 expression.
“we detected increased enrichment of H3S28P in sites with chromatin opening upon SOX9 expression”
Quote in the paperSubstantial claim - Findingown data
One half-site in the retrieved SOX9 dimer motif lacked the 'G' nucleotide from the canonical Ca/tTTGT motif.
“one of the half-sites in this dimer motif was lacking the ‘G’ nucleotide from the canonical Ca/tTTGT motif”
Quote in the paperNot a substantial claim - Findingown data
The SOX dimer motif was not among the top enriched motifs but was listed further down with a P-value of 1e-4.
“The SOX dimer motif was not enriched as one of the top motifs but listed further down on the list (P-value 1e–4).”
Quote in the paperNot a substantial claim- Rests on an assumption: The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
- Findingown data
H3S28P completely abolished SOX9 binding, both alone and in combination with other histone modifications.
“H3S28P completely abolished SOX9 binding, both when the modification was present alone and in combination with other histone modifications”
Quote in the paperSubstantial claim - Findingown data
Genes associated with regions of increased chromatin accessibility in EC8 that contained SOX motifs were linked to mesenchymal transition.
“Furthermore, genes associated with regions of increased chromatin accessibility in EC8 that contained SOX motifs, were linked to mesenchymal transition (Supplementary Figure S7A).”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
- Findingown data
SOX9 chromatin binding is transient and dynamic.
“we observed transient and dynamic chromatin binding by SOX9.”
Quote in the paperSubstantial claim - Findingown data
In HUVECs, SOX9 induced expression of a plethora of TFs associated with mesenchyme, including PRRX1, PKNOX2, FOXC1 and other SOX TFs, such as SOX5 and SOX6.
“In HUVECs, SOX9 induced expression of a plethora of TFs associated with mesenchyme, including PRRX1, PKNOX2, FOXC1 and other SOX TFs, such as SOX5 and SOX6.”
Quote in the paperSubstantial claim - Findingown data
None of the other SOX factors showed the same expression pattern as SOX9, being unique to EC8 and Fibro.
“Of note, none of the other SOX factors showed the same expression pattern as SOX9, being unique to EC8 and Fibro (Supplementary Figure S7B), suggesting SOX9 is involved in chromatin opening in endothelial cells in lesions to promote a mesenchymal cell phenotype during atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
- Findingown data
Closing of chromatin mainly occurred at 96 h post-transduction.
“Closing of chromatin, on the other hand, mainly occurred at 96h post-transduction.”
Quote in the paperNot a substantial claim - Findingown data
Some TFs with known functions in EndMT/EMT, such as SNAI1 and ZEB1, were downregulated in our dataset.
“Interestingly, some TFs with known functions in EndMT/EMT, such as SNAI1 and ZEB1, were downregulated in our dataset.”
Quote in the paperSubstantial claim - Findingown data
C2 regions were enriched for the histone variant H2A.Z.
“C2 regions were enriched for the histone variant H2A.Z”
Quote in the paperSubstantial claim - Findingown data
SOX9 bound most histone tail modifications as well as unmodified histone tails.
“SOX9 bound most histone tail modifications as well as the unmodified histone tails”
Quote in the paperSubstantial claim - Findingown data
SOX9 physically associated with H3K4me1, H3K4me3 and H3K27ac in E12.5 mouse cardiac cushions and in SOX9-expressing HUVECs.
“We observed physical association of SOX9 with histone modifications H3K4me1, H3K4me3 and H3K27ac in E12.5 mouse cardiac cushions and in SOX9-expressing HUVECs”
Quote in the paperSubstantial claim - Findingown data
SOX motifs were significantly enriched in regions that became newly accessible in EC8 only.
“Interestingly, SOX motifs were significantly enriched in regions that became newly accessible in EC8 only (Figure 8C).”
Quote in the paperSubstantial claim- Rests on an assumption: The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
- Findingown data
Phosphorylation of H3S28 abolished SOX9 binding to histone tails in vitro and in vivo.
“However, phosphorylation of H3S28 abolished SOX9 binding to histone tails in vitro and in vivo.”
Quote in the paperSubstantial claim - Findingown data
H2A.Z was observed at active promoters and enhancers in our C1 cluster.
“which we observed in our C1 cluster.”
Quote in the paperNot a substantial claim - Findingnone given
We could not identify specific histone tail modifications that were required for SOX9 binding.
“We could not identify specific histone tail modifications that were required for SOX9 binding.”
Quote in the paperNot a substantial claim - Findingown data
Pioneering by SOX9 predominantly occurred in distal regions with enrichment of the histone variant H2A.Z.
“Pioneering by SOX9 predominantly occurred in distal regions with enrichment of the histone variant H2A.Z.”
Quote in the paperSubstantial claim - Findingown data
The monomer motif was more enriched in regions where SOX9 bound but did not open chromatin.
“which is in line with our observation that the monomer motif was more enriched in regions where SOX9 bound but did not open chromatin.”
Quote in the paperSubstantial claim - Findingown data
H3S28P was enriched at sites where SOX9 opened chromatin.
“Interestingly, we observed increased enrichment of H3S28P at sites where SOX9 opened chromatin, suggesting that following chromatin opening, H3S28 is phosphorylated and SOX9 is evicted from the site.”
Quote in the paperNot a substantial claim - Findingown data
SOX9 chromatin binding is highly dynamic.
“Our time-course revealed that SOX9 chromatin binding is highly dynamic.”
Quote in the paperSubstantial claim - Interpretationown data
In this context, upregulation of mesenchymal markers does not depend on SNAI1 and ZEB1.
“indicating that upregulation of mesenchymal markers does not depend on these TFs in this context.”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 opens chromatin to drive EndMT in atherosclerotic lesions in vivo.
“Finally, our analysis of single-cell chromatin accessibility indicates that SOX9 opens chromatin to drive EndMT in atherosclerotic lesions in vivo.”
- Also stated in: § SOX9 expression is induced in endothelial cells during EndMT in vivo · boosted
“The above results confirm that SOX9 expression is induced in endothelial cells and plays a role in the early steps of EndMT both during embryonic heart valve development and in atherosclerotic lesions.”
Quote in the paperSubstantial claim - Also stated in: § SOX9 expression is induced in endothelial cells during EndMT in vivo · boosted
- Interpretationown data
Gene programs activated by SOX9 expression in HUVECs are similar to those that drive EndMT in atherosclerosis.
“This suggests that gene programs activated by SOX9 expression in HUVECs are similar to those that drive EndMT in atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: SOX9 expression in HUVECs is a valid model for EndMT in atherosclerosis.
- Rests on an assumption: The scRNA-seq data from atherosclerotic lesions accurately distinguish fibroblasts from endothelial cells.
- Interpretationreasoning
Genes associated with C2 regions were more specifically linked to a transition to a mesenchymal fate.
“In contrast, genes associated with C2 regions were more specifically linked to a transition to a mesenchymal fate.”
Quote in the paperNot a substantial claim - Interpretationown data
Newly opened chromatin regions suggest pioneer TF activity by SOX9.
“These newly opened chromatin regions suggest pioneer TF activity by SOX9.”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 expression is sufficient to induce EndMT by causing a switch in chromatin states.
“our analysis of the transcriptome and epigenetic landscape show that SOX9 expression is sufficient to induce EndMT by causing a switch in chromatin states.”
Quote in the paperSubstantial claim- Rests on an assumption: SOX9 expression in HUVECs is a valid model for EndMT in atherosclerosis.
- Interpretationown data
Using EChO within SOX9 data, fragment sizes mostly ranged between 50 and 150 bp, indicating binding by SOX9 to both nucleosomes and open DNA.
“we observed a distribution of fragment sizes mostly ranging between 50 and 150 bp, indicating binding by SOX9 to both nucleosomes and open DNA”
Quote in the paperSubstantial claim - Interpretationreasoning
The presence of monomer motifs in regions where SOX9 is binding and possibly scanning but not opening closed chromatin may explain why SOX9 is pausing at these sites.
“the presence of monomer motifs in regions where SOX9 is binding and possibly scanning but not opening closed chromatin may explain why SOX9 is pausing at these sites.”
Quote in the paperNot a substantial claim - Interpretationreasoning
These 3548 regions, in addition to the 336 C2 regions, are sites where SOX9 may act as a pioneer TF.
“These 3548 regions, in addition to the 336 C2 regions, are sites where SOX9 may act as a pioneer TF.”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 can induce opening of chromatin and deposition of active histone modifications at previously silent binding sites.
“By using genome-wide techniques, we show that SOX9 can induce opening of chromatin and deposition of active histone modifications at previously silent binding sites.”
Quote in the paperSubstantial claim - Interpretationown data
Motif analysis of remaining regions still showed SOX dimer motifs as top enriched motifs, emphasizing transient chromatin binding by SOX9.
“Motif analysis of the remaining regions still showed SOX dimer motifs as the top enriched motifs, emphasizing transient chromatin binding by SOX9”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 expression in human endothelial cells can drive EndMT by altering the chromatin landscape.
“In this study, our analyses provide evidence that SOX9 expression in human endothelial cells can drive EndMT by altering the chromatin landscape.”
Quote in the paperSubstantial claim - Interpretationreasoning
Activation of these chromatin regions drives expression of mesenchymal genes.
“The activation of these chromatin regions drives expression of mesenchymal genes, highlighting the ability of one single TF to induce major chromatin restructuring and cell fate decisions.”
Quote in the paperSubstantial claim - Interpretationreasoning
SOX9 is involved in chromatin opening in endothelial cells in lesions to promote a mesenchymal cell phenotype during atherosclerosis.
“suggesting SOX9 is involved in chromatin opening in endothelial cells in lesions to promote a mesenchymal cell phenotype during atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Enrichment of SOX motifs in newly accessible chromatin regions indicates that SOX9 is the factor opening those regions in lesions.
- Interpretationown data
SOX9 is not dependent on enrichment of specific histone tail modifications to bind chromatin.
“SOX9 is not dependent on enrichment of specific histone tail modifications to bind chromatin.”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 expression in endothelial cells is driving EndMT in atherosclerotic lesions.
“Moreover, by analysing available scRNA-seq datasets, we propose that SOX9 expression in endothelial cells is driving EndMT in atherosclerotic lesions supporting a role of SOX9 in pathological processes.”
Quote in the paperSubstantial claim- Rests on an assumption: Enrichment of SOX motifs in newly accessible chromatin regions indicates that SOX9 is the factor opening those regions in lesions.
- Interpretationreasoning
SOX9 may be a potential driver of disease mechanisms when aberrantly expressed in endothelial cells.
“Thus, SOX9 may be a potential driver of disease mechanisms when aberrantly expressed in endothelial cells.”
Quote in the paperSubstantial claim - Interpretationcitation
Pioneering may be viewed as a one-time event, meaning that SOX9 does not need to remain bound at sites once opened.
“Dynamic chromatin binding has been observed for other pioneer TFs (47) and pioneering may be viewed as a one-time event, meaning that SOX9 does not need to remain bound at sites once opened.”
Quote in the paperSubstantial claim - Interpretationown data
SOX9 is a driver of EndMT in atherosclerosis.
“Furthermore, our analysis of single-cell data points to SOX9 as a driver of EndMT in atherosclerosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Enrichment of SOX motifs in newly accessible chromatin regions indicates that SOX9 is the factor opening those regions in lesions.
- Classified as probably not a substantial claim. 33
- May combine two claims. 74
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSOX9 expression in endothelial cells induces skin wound healing.
“Recently, SOX9 expression in endothelial cells was also found to induce skin wound healing (16).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Zhao, 2021, Sox9 and rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors, Nat. Commun. source
The Results section, “Loss of Sox9 in the endothelium significantly impairs EndMT and reduces scarring during wound healing” (page not provided), reports the opposite direction: mice lacking endothelial Sox9 healed skin wounds significantly faster than controls. The paper also reports enhanced healing after Sox9 inhibition with siRNA. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mouse, SOX9 is essential in skin wound healing.
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [11] Akiyama, 2004, Essential role of sox9 in the pathway that controls formation of cardiac valves and septa, Proc. Natl. Acad. Sci. U.S.A. source
The Results describe Sox9’s role in mouse endocardial cushion formation and cardiac EMT, not skin wound healing. Searches for “skin wound healing” and related skin and wound-repair terms found no passage in our copy addressing the claimed role in healing. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [16] Zhao, 2021, Sox9 and rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors, Nat. Commun. source
The Results section, “Loss of Sox9 in the endothelium significantly impairs EndMT and reduces scarring during wound healing” (page unavailable), reports that mice with endothelial Sox9 deletion healed skin wounds significantly faster than controls. Topical Sox9 inhibition likewise accelerated closure. The paper therefore does not support the claim that SOX9 is essential for skin wound healing in mice. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [17] Garside, 2015, SOX9 modulates the expression of key transcription factors required for heart valve development, Development source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSOX9 can drive cancer invasion and metastasis in multiple cancers, including prostate, breast, colon, gastric, and lung.
“SOX9 can drive cancer invasion and metastasis in multiple cancers, including prostate, breast, colon, gastric, and lung (summarized in (13))”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Aguilar-Medina, 2019, SOX9 stem-cell factor: clinical and functional relevance in cancer, J. Oncol. source
The Concluding Remarks (no page supplied) link SOX9 to metastasis in breast, gastric, and colorectal cancer. Section 3.4 describes its promotion of gastric invasion and metastasis, and section 3.6 suggests a role in prostate invasion. The cited paper does not establish the claimed invasion-and-metastasis role in lung cancer, and its prostate discussion does not establish metastasis. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA CD mutation affecting SOX9 dimerization impairs chromatin remodeling and transcriptional activation by SOX9.
“In the same study, a CD mutation which affects SOX9 dimerization was shown to impair chromatin remodeling and transcriptional activation by SOX9.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSOX9 remodeled chromatin and activated transcription at the COL2A1 enhancer on an in vitro assembled chromatin template.
“SOX9 remodeled chromatin and activated transcription at this site on an in vitro assembled chromatin template (18).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Coustry, 2010, The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template, Nucleic Acids Res. source
May combine two claims.
PremisecitationDuring cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and SOX9 activates transcription of key regulators of heart valve development.
“During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and where SOX9 activates transcription of key regulators of heart valve development (11,17).”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationSOX9 is crucial for EMT and EndMT.
“SOX9 is also crucial for processes involving epithelial-to-mesenchymal transition (EMT) and the closely related process endothelial-to-mesenchymal transition (EndMT) (10–12).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [10] Lincoln, 2007, Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development, Dev. Biol. source
- cites [11] Akiyama, 2004, Essential role of sox9 in the pathway that controls formation of cardiac valves and septa, Proc. Natl. Acad. Sci. U.S.A. source
The paper states that Sox9 has an essential role in EMT in the heart, specifically in endocardial endothelial cells forming cardiac cushions (opening section; Discussion). This supports its importance in cardiac EndMT, but the paper only suggests analogous roles in other organs; it does not establish that SOX9 is crucial for EMT more generally. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [12] Cheung, 2005, The transcriptional control of trunk neural crest induction, survival, and delamination, Dev. Cell source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn chondrogenic systems, SOX9 can activate enhancers but may not be required for initiation of chromatin changes.
“In chondrogenic systems, SOX9 can activate enhancers (19), but may not be required for the initiation of chromatin changes (20).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [19] Cheung, 2020, Histone chip-Seq identifies differential enhancer usage during chondrogenesis as critical for defining cell-type specificity, FASEB J. source
- cites [20] Liu, 2018, SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis, Development source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSOX9 is involved in promoting liver and cardiac fibrosis by stimulating ECM deposition.
“and is involved in promoting liver and cardiac fibrosis by stimulating ECM deposition (14,15).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [14] Lee, 2011, Mechanisms of hepatic fibrogenesis, Best Pract. Res. Clin. Gastroenterol. source
The Introduction and Fibrogenic Signaling Pathways section describe extracellular-matrix deposition as a mechanism of liver fibrosis. But the Transcription Factors section does not identify SOX9, and the searched passages do not address cardiac fibrosis. The source therefore supports the general liver-fibrosis mechanism, not the claim that SOX9 promotes liver and cardiac fibrosis through it. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [15] Lacraz, 2017, Tomo-Seq identifies SOX9 as a key regulator of cardiac fibrosis during ischemic injury, Circulation source
May combine two claims.
Findingown dataGenes possibly repressed by SOX9 include endothelial markers VWF and PECAM1, as well as genes encoding TFs important for endothelial cell functions, including ERG and ETS2.
“Genes possibly repressed by SOX9 include endothelial markers, such as VWF and PECAM1, as well as genes encoding TFs important for endothelial cell functions, including ERG (60) and ETS2 (61).”
Quote in the paperSubstantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPRRX1 and PKNOX2 have roles in mesenchyme development.
“both of which have roles in mesenchyme development (56,57)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [56] Lu, 1999, prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme, Development source
- cites [57] Zhou, 2013, Misexpression of pknox2 in mouse limb bud mesenchyme perturbs zeugopod development and deltoid crest formation, PLoS One source
The Results and Discussion show that altering Pknox2 expression in mouse limb-bud mesenchyme perturbs skeletal development, supporting a developmental role for PKNOX2. The paper uses the Prx1 promoter to drive that expression, but the cited passages do not establish a developmental role for PRRX1 itself. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPRRX1 promotes EMT in cancers.
“while PRRX1 also promotes EMT in cancers (58,59).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [58] Reichert, 2013, The prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis, Genes Dev. source
The Results section reports that Prrx1 isoforms increase migration and invasion in pancreatic cancer cells, and that Prrx1b overexpression disrupts cyst organization. These findings support related cancer-cell behaviours, but our copy does not show that PRRX1 promotes epithelial-to-mesenchymal transition (EMT), nor does it establish the claim across cancers generally. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [59] Takahashi, 2013, Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer, Br. J. Cancer source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA half-site lacking the 'G' nucleotide from the canonical Ca/tTTGT motif has been observed at sites of nucleosomal binding by SOX2.
“which has also been observed at sites of nucleosomal binding by the pioneer and pluripotency factor SOX2 (64).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [64] Soufi, 2015, Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming, Cell source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mouse, SOX9 is essential for the EndMT process that produces functioning heart valves.
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [11] Akiyama, 2004, Essential role of sox9 in the pathway that controls formation of cardiac valves and septa, Proc. Natl. Acad. Sci. U.S.A. source
The paper’s introductory passage states that Sox9 has an essential role in cardiac EMT, and describes endocardial cushions as the primordia of valves and septa. The Results report hypoplastic cushions in Sox9-null mouse embryos. The copy does not establish that this process produces functioning valves or assess valve function. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [16] Zhao, 2021, Sox9 and rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors, Nat. Commun. source
The Discussion reports that deleting Sox9 in mouse endothelium substantially reduced EndMT and scarring, supporting a role for SOX9 in murine EndMT and wound healing. It does not establish that SOX9 is essential for the EndMT that produces functioning heart valves; its discussion of cardiac cushion EndMT concerns Slug rather than a SOX9 valve experiment (page unavailable in our copy). (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [17] Garside, 2015, SOX9 modulates the expression of key transcription factors required for heart valve development, Development source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn mouse chondrocytes, a SOX motif was enriched in distal regions while promoter regions were enriched for motifs suggesting binding of SOX9 through the basal transcriptional machinery.
“In mouse chondrocytes, a SOX motif was enriched in distal regions while promoter regions were enriched for motifs suggesting binding of SOX9 through the basal transcriptional machinery (62).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [62] Ohba, 2015, Distinct transcriptional programs underlie sox9 regulation of the mammalian chondrocyte, Cell Rep. source
The Results sections on Class I targets and Sox9 peaks report Sox motif enrichment away from promoters, but not in transcription-start-site-proximal regions. The Discussion proposes that Sox9 associates with promoters through protein–protein interactions with the basal transcription apparatus. It does not report enrichment of promoter motifs as the basis for that proposal. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBoth SNAI1 and SNAI2 are required for EndMT in cardiac cushion morphogenesis in mice.
“Interestingly, both SNAI1 and SNAI2 are required for EndMT in cardiac cushion morphogenesis in mice (67).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [67] Niessen, 2008, Slug is a direct notch target required for initiation of cardiac cushion cellularization, J. Cell Biol. source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationH3S28P is associated with open chromatin and activation of transcription.
“H3S28P, which is associated with open chromatin and activation of transcription (65)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [65] Josefowicz, 2016, Chromatin kinases act on transcription factors and histone tails in regulation of inducible transcription, Mol. Cell source
The Results section on lineage-specific and stimulation-responsive chromatin reports that H3S28ph correlates with LPS-induced transcription. The Discussion suggests it may make chromatin more permissive, but treats increased chromatin-fiber accessibility as a possibility rather than establishing an association with open chromatin. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationPioneer TFs have the unique ability to engage their target sites in closed chromatin, render them accessible and allow other factors to bind.
“Pioneer TFs have the unique ability to engage their target sites in closed chromatin, render them accessible and allow other factors to bind (68).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [68] Iwafuchi-Doi, 2019, The mechanistic basis for chromatin regulation by pioneer transcription factors, Wiley Interdiscip. Rev. Syst. Biol. Med. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies found that 20-30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes.
“Previous studies of genome-wide chromatin binding by SOX9 found that 20–30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes (17,62).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe pluripotency factors OCT4, SOX2, and KLF4, when acting as pioneer TFs, bind nucleosomes in vitro by targeting partial and degenerate DNA motifs displayed on the nucleosome surface.
“The pluripotency factors OCT4, SOX2, and KLF4, when acting as pioneer TFs, bind nucleosomes in vitro by targeting partial and degenerate DNA motifs displayed on the nucleosome surface (64).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [64] Soufi, 2015, Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming, Cell source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationH2A.Z destabilizes nucleosomes and is often found at active promoters and enhancers.
“H2A.Z has been shown to destabilize nucleosomes and is often found at active promoters and enhancers (71), which we observed in our C1 cluster.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [71] Martire, 2020, The roles of histone variants in fine-tuning chromatin organization and function, Nat. Rev. Mol. Cell Biol. source
The Nucleosome structure and dynamics section (page not provided) says H2A.Z can destabilize nucleosomes and is deposited at enhancers and promoters. It does not specify that those sites are active, and it notes that homotypic H2A.Z nucleosomes are more stable; the destabilization finding applies to particular nucleosome compositions. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn gonadal cell fate transition, DMRT1 opens chromatin to allow binding of SOX9, while SOX9 did not have strong pioneering abilities.
“In gonadal cell fate transition, DMRT1 was shown to open chromatin to allow binding of SOX9, while SOX9 did not have strong pioneering abilities (74).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [74] Lindeman, 2021, The conserved sex regulator DMRT1 recruits SOX9 in sexual cell fate reprogramming, Nucleic Acids Res. source
The Results section reports that SOX9 binding at many Sertoli-biased regions was strongly DMRT1-dependent, and the Discussion says SOX9 alone could not make many such regions accessible in cultured postnatal granulosa cells. But the paper presents DMRT1’s chromatin-opening pioneer mechanism as a favored interpretation requiring biochemical confirmation, not as established; it also notes that SOX9’s dependence on DMRT1 may differ in fetal gonads. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationH2A.Z occupancy seems to correlate with pioneer TF binding to nucleosome-occupied regions and has been suggested to act as a scaffold for binding of pioneer TFs and chromatin remodelers.
“The role of H2A.Z in closed chromatin is less clear, but H2A.Z occupancy seems to correlate with pioneer TF binding to nucleosome-occupied regions and has been suggested to act as a scaffold for binding of pioneer TFs and chromatin remodelers (72,73).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [72] Cauchy, 2017, Two possible modes of pioneering associated with combinations of H2A.Z and p300/CBP at nucleosome-occupied enhancers, Transcription source
The Results and discussion (page unavailable) report H2A.Z enrichment at nucleosome-occupied sites bound by the pioneer factors Ets1 and Oct4, supporting the proposed correlation. The Introduction and Results and discussion mention pioneer factors recruiting chromatin remodelers, but do not suggest that H2A.Z acts as a scaffold for binding either the factors or remodelers. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [73] Subramanian, 2015, H2A.Z: a molecular rheostat for transcriptional control, F1000Prime Rep source
May combine two claims.
Findingown dataChanges in the chromatin landscape and cell fate induced by SOX9 are persistent.
“However, while SOX9 binding is dynamic, changes in the chromatin landscape and cell fate induced by SOX9 are persistent.”
- Also stated in: § Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype · hedged
“Notably, the cells could be passaged without reverting to their original morphology, suggesting the mesenchymal morphology induced by SOX9 was permanent and robust.”
Quote in the paperSubstantial claim- Also stated in: § Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype · hedged
May combine two claims.
Findingown dataSOX9 chromatin binding is highly transient and dynamic, possibly promoted through its eviction by histone phosphorylation.
“We further observe highly transient and dynamic SOX9 binding, possibly promoted through its eviction by histone phosphorylation.”
- Also stated in: § INTRODUCTION · plain
“Furthermore, we show that SOX9 chromatin binding is highly dynamic, but nevertheless causes stable changes in the chromatin landscape.”
Quote in the paperSubstantial claim- Also stated in: § INTRODUCTION · plain
May combine two claims.
Findingown dataAt E9.5, ERG is expressed in all endothelial cells and downregulated within emerging mesenchymal cells, which express SOX9 as they undergo EndMT and populate the cardiac cushions.
“At E9.5, the endothelial master TF ERG was expressed in all endothelial cells and downregulated within emerging mesenchymal cells, which expressed SOX9 as they underwent EndMT and populated the cardiac cushions (Figure 1A, left panel).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9-expressing HUVECs had increased migratory properties and downregulated expression of CD31 and ERG.
“As expected, increased migratory properties (Figure 1E) and downregulated expression of the endothelial surface protein CD31 as well as ERG occured in SOX9-expressing cells (Figure 1F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9 displays features of a pioneer transcription factor, including opening chromatin and leading to deposition of active histone modifications at silent chromatin regions, guided by SOX dimer motifs and H2A.Z enrichment.
“By genome-wide mapping of the chromatin landscape, we show that SOX9 displays features of a pioneer transcription factor, such as opening of chromatin and leading to deposition of active histone modifications at silent chromatin regions, guided by SOX dimer motifs and H2A.Z enrichment.”
- Also stated in: § INTRODUCTION · hedged
“Altogether, we find that at a subset of regions that are silent in unstimulated HUVECs, SOX9 occupancy increases chromatin accessibility and enrichment of active histone modifications to induce expression of mesenchymal genes, suggesting SOX9 has the ability to act as a pioneer TF to reprogram cell fate.”
Quote in the paperSubstantial claim- Also stated in: § INTRODUCTION · hedged
May combine two claims.
Findingown dataSOX9 expression resulted in enhanced expression of mesenchymal genes, with concurrent downregulation of endothelial gene expression.
“SOX9 expression resulted in enhanced expression of mesenchymal genes, with concurrent downregulation of endothelial gene expression (Figure 2E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBy E10.5, fewer cells co-express SOX9 and ERG, and SOX9-expressing mesenchymal cells have proliferated, populating the cardiac cushion.
“By E10.5, we detected fewer cells co-expressing SOX9 and ERG, and the SOX9-expressing mesenchymal cells had proliferated, populating the cardiac cushion (Figure 1A, right panel).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGenes upregulated in response to SOX9 were significantly enriched for hallmark EMT gene sets and mesenchymal cell type signature gene sets, with fibroblast-like cell as top enriched cell type.
“Genes upregulated in response to SOX9 were significantly enriched for hallmark gene sets for EMT (Figure 2C) and cell type signature gene sets of mesenchymal cells, with fibroblast-like cell as the top enriched cell type (Figure 2D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9-expressing HUVECs had high Periostin levels, while Vimentin levels were slightly higher.
“These cells also had high Periostin levels, while Vimentin levels were slightly higher.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9 transcripts were detected at significant levels in EC8, Fibro and SMC clusters in Andueza et al. data and EC6, Fibro, and SMC clusters in Chen et al. data.
“Of note, SOX9 transcripts were detected at significant levels in EC8, Fibro and SMC clusters in the Andueza et al. data and EC6, Fibro, and SMC clusters in the Chen et al. data (Figure 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataC2 regions (10%) had closed chromatin and no enrichment of assayed modifications, but with SOX9 bound they gained high chromatin accessibility and enrichment of H3K4me1 and H3K27ac.
“C2 regions (10%) had closed chromatin and no enrichment of the assayed modifications, but with SOX9 bound they gained high chromatin accessibility and enrichment of H3K4me1 and H3K27ac.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX motifs were significantly enriched in C1 and C2 regions, with the highest number in C2 regions.
“Motif analysis revealed that SOX motifs were significantly enriched in C1 and C2 regions, with the highest number in C2 regions”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe defined and degenerate dimer motifs were the top two enriched motifs, with a larger percentage of C2 regions containing these motifs; C2 also had a SOX monomer motif enriched as the fourth most significant.
“The defined and the degenerate dimer motifs identified in Supplementary Figure S3E were the top two enriched motifs, with a larger percentage of C2 regions containing these motifs. C2 regions also had a SOX monomer motif enriched as the fourth most significant.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe C4 cluster, composed of over 50% of SOX9 bound regions, was closed with low levels of histone modifications and did not show changes with SOX9 binding.
“The final C4 cluster, composed of over 50% of SOX9 bound regions, was closed with low levels of histone modifications and did not show changes with SOX9 binding.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMost members of these TF families were highly expressed in HUVECs and downregulated upon SOX9 expression.
“Most members of these TF families were highly expressed in HUVECs and downregulated upon SOX9 expression”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRegions with altered chromatin accessibility were exclusively distal and enriched GO terms for associated genes showed a clear link to EndMT processes.
“Regions with altered chromatin accessibility were exclusively distal and enriched GO terms for the associated genes showed a clear link to EndMT processes”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data17% of upregulated genes associated with C2 regions were silent prior to SOX9 binding, while only 7% of upregulated C1 genes were silent before.
“17% of the upregulated genes associated with C2 regions were silent prior to SOX9 binding, while only 7% of the upregulated C1 genes were silent before”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOf genes with both a SOX9 bound region and differential gene expression, 543 genes (63%) were upregulated by SOX9, while 324 genes (37%) were downregulated.
“Of these, 543 genes (63%) were upregulated by SOX9, while 324 genes (37%) were downregulated.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWe identified direct SOX9 target genes, most of which were upregulated by SOX9 and many of which have known roles in mesenchymal cells.
“we identified direct SOX9 target genes, most of which were upregulated by SOX9 and many of which have known roles in mesenchymal cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataC3 and C4 regions did not show evidence of SOX motif enrichment and had fewer motifs significantly enriched overall.
“C3 and C4 regions did not show evidence of SOX motif enrichment and had fewer motifs significantly enriched overall.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGenes associated with C1 and C2 regions were enriched for processes connected with mesenchymal cell identity, with C2 most enriched for developmental processes and C1 enriched for cellular organization.
“Genes associated with C1 and C2 regions were enriched for processes connected with mesenchymal cell identity, with C2 regions most enriched for developmental processes and C1 enriched for cellular organization”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataC1 regions (12%) contain high chromatin accessibility regardless of SOX9 presence, with high H3K4me1 and H3K27ac that increased slightly with SOX9 occupancy.
“The first cluster, C1 (12%), contains regions with high chromatin accessibility regardless of SOX9 presence”
- Also stated in: § SOX9 opens chromatin at a subset of binding sites in closed chromatin · plain
“We also observed high levels of H3K4me1 and H3K27ac in these regions, indicative of active regulatory regions, which increased slightly with SOX9 occupancy.”
Quote in the paperNot a substantial claim- Also stated in: § SOX9 opens chromatin at a subset of binding sites in closed chromatin · plain
May combine two claims.
Findingown dataSOX motifs were the top three enriched motifs in SOX9 peaks, including two dimer and one monomer SOX motif.
“we identified SOX motifs as the top three enriched (Supplementary Figure S3E), including two dimer (one defined and one more degenerate) and one monomer SOX motif”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOver 70% of genes with C1 or C2 type SOX9 binding were expressed, while only ∼50% of C3 or C4 genes were expressed in either condition.
“While over 70% of genes with C1 or C2 type SOX9 binding were expressed, only ∼50% of C3 or C4 genes were expressed in either condition”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9 was not bound to the known enhancer of COL2A1, although COL2A1 was highly upregulated with SOX9 expression.
“we did not observe SOX9 bound to the known enhancer of the well-characterized SOX9 target gene, COL2A1, although this gene was highly upregulated with SOX9 expression.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe MMP2 locus had two C4 regions in addition to a C2 region and was highly upregulated with SOX9 expression.
“The MMP2 locus is an interesting example as it had two C4 regions in addition to a C2 region and this gene was highly upregulated with SOX9 expression.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataC3 regions (23%) consisted of closed chromatin and no active histone modifications but high H3K27me3; neither chromatin accessibility, active histone modifications, nor H3K27me3 levels were affected by SOX9 binding.
“C3 (23%) consisted of regions in closed chromatin and no active histone modifications but high enrichment of the repressive H3K27me3”
- Also stated in: § SOX9 opens chromatin at a subset of binding sites in closed chromatin · plain
“Neither chromatin accessibility, active histone modifications, nor H3K27me3 levels were affected by SOX9 binding.”
Quote in the paperSubstantial claim- Also stated in: § SOX9 opens chromatin at a subset of binding sites in closed chromatin · plain
May combine two claims.
Findingown dataMany opened chromatin regions were bound by SOX9 at 48h only, and multiple patterns of SOX9 binding were transient and dynamic.
“Many opened chromatin regions were bound by SOX9 at 48h only, but we observed multiple patterns of SOX9 binding that were strikingly transient and dynamic.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataInduction of chromatin opening predominantly occurred at 48 h, coinciding with SOX9 chromatin binding.
“Induction of chromatin opening predominantly occurred at 48 h, coinciding with SOX9 chromatin binding.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataVery few SOX9 bound regions localized to open chromatin regions in HUVECs and were rarely found in promoter regions of genes.
“Surprisingly, very few SOX9 bound regions localized to open chromatin regions in HUVECs and were rarely found in promoter regions of genes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOX9 mRNA and protein were detectable after 24 h.
“SOX9 mRNA and protein were detectable after 24 h (Figure 6C)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt the LGALS3 locus, three SOX9 bound regions in closed chromatin were detected, but only the region containing H2A.Z became opened with SOX9 binding.
“we detected three SOX9 bound regions upstream of the LGALS3 locus in closed chromatin, but only the region containing H2A.Z became opened with SOX9 binding.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe requirement for H2A.Z enrichment and dimer motif presence for SOX9 chromatin opening and activation of target enhancers is evident from our study.
“Whether SOX9 requires destabilized nucleosomes for chromatin opening and activation of target enhancers remains undetermined, but the requirement for H2A.Z enrichment and dimer motif presence is evident from our study.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChromatin remained open after SOX9 was no longer bound and cell morphology changes persist.
“However, chromatin remained open after SOX9 was no longer bound and cell morphology changes persist.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEctopic SOX9 expression in endothelial cells is sufficient to activate mesenchymal genes and steer endothelial cells towards a mesenchymal fate.
“Using human umbilical vein endothelial cells (HUVECs) as an EndMT model, we show that SOX9 expression alone is sufficient to activate mesenchymal genes and steer endothelial cells towards a mesenchymal fate.”
- Also stated in: § Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype · hedged
“This suggests that ectopic expression of SOX9 in endothelial cells is sufficient for and efficient at direct reprogramming to a mesenchymal cell fate.”
- Also stated in: § Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype · plain
“Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype”
Quote in the paperSubstantial claim- Also stated in: § Ectopic SOX9 expression in endothelial cells promotes a mesenchymal phenotype · hedged
Classified as probably not a substantial claim.
Study design and conductown dataHUVECs were transduced with lentiviral supernatants titrated to transduce >95% of cells, indicated by GFP expression.
“HUVECs were plated in six-well plates and lentiviral supernatants were titrated to transduce >95% of the cells (indicated by GFP expression).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationSome developmental TFs can reprogram one cell type into another by engaging developmentally silent genes in closed chromatin, acting as pioneer TFs.
“Some developmental TFs have the remarkable ability to reprogram one cell type into another by engaging genes that are developmentally silent and in closed chromatin, thus acting as pioneer TFs to initiate transcriptional events (21).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Iwafuchi-Doi, 2016, Cell fate control by pioneer transcription factors, Development source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataCUT&Tag was performed with two biological replicates.
“Two biological replicates were sequenced.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataSOX9 overexpression was confirmed by western blotting and RT-qPCR.
“SOX9 overexpression was confirmed by western blotting and RT-qPCR (described in Supplemental Material).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataCUT&RUN was performed with two biological replicates of SOX9 at 96 h and one replicate of the SOX9 time-course.
“Two biological replicates of SOX9 at 96 h and one replicate of the SOX9 time-course were sequenced.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRNA-seq was performed with three biological replicates.
“Three biological replicates were sequenced.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataMany endothelial cells lining the cardiac cushions express both SOX9 and ERG, suggesting SOX9 expression is induced in endothelial cells lining the cardiac cushions prior to overt EndMT and continues through the transition into migrating mesenchymal cells.
“Interestingly, many endothelial cells lining the cushions expressed both SOX9 and ERG, suggesting SOX9 expression is induced in endothelial cells lining the cardiac cushions, prior to overt EndMT, and continues to be expressed through the transition into migrating mesenchymal cells.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationSOX9 acts as a master regulator in heart valve development, binding regulatory regions that control TFs important for proper valve development, but its impact on the chromatin landscape is not yet characterized.
“SOX9 acts as a master regulator in heart valve development, binding regulatory regions that control TFs important for proper valve development, but its impact on the chromatin landscape is not yet characterized (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Garside, 2015, SOX9 modulates the expression of key transcription factors required for heart valve development, Development source
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.
Study design and conductown dataATAC-seq was performed with two biological replicates.
“Two biological replicates were sequenced.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataSOX9 binds directly to DNA in open chromatin regions, including regions opened with SOX9 binding (C2), suggesting capture of SOX9 binding following chromatin opening in C2.
“This indicates that SOX9 binds directly to DNA in open chromatin regions, including the regions that were opened with SOX9 binding (C2), suggesting that we capture SOX9 binding following chromatin opening in C2.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAverage SOX9 signal was lower in C3 and C4 regions compared to C1 and C2, suggesting lower-affinity binding events.
“We observed lower average SOX9 signal in C3 and C4 regions compared to C1 and C2, suggesting the former are lower-affinity binding events (Figure 4F)”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAt a subset of silent regions, SOX9 increases chromatin accessibility, suggesting a role as a pioneer TF.
“At a subset of these silent regions, SOX9 increases chromatin accessibility, suggesting a role as a pioneer TF.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe low overlap suggests either other TFs are responsible for chromatin opening downstream of SOX9 or SOX9 binding at these regions is transient.
“suggesting that either other TFs are responsible for chromatin opening downstream of SOX9 or SOX9 binding at these regions is transient, allowing SOX9 to bind, open and activate chromatin and then leave.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningC1 genes were already expressed prior to SOX9 binding, leading to further upregulation.
“The latter may reflect that C1 genes were already expressed prior to SOX9 binding, leading to further upregulation.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe SOX9-induced switch in chromatin states leads to activation of mesenchymal genes and downregulation of endothelial genes.
“This leads to activation of mesenchymal genes and downregulation of endothelial genes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe regulatory elements activated by SOX9 drive expression of mesenchymal genes and lead to a transition in cell fate.
“The regulatory elements activated by SOX9 drive expression of mesenchymal genes and lead to a transition in cell fate.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEChO analysis revealed smaller average fragment size (<100 bp) for C1 and C2 regions, reflective of direct DNA binding, and larger average fragment size (∼150 bp) for C3 and C4 regions, suggesting binding by SOX9 to nucleosomal DNA.
“EChO analysis for clusters C1–C4 revealed a smaller average fragment size (<100 bp) for the regions in C1 and C2, reflective of direct DNA binding, and a larger average fragment size (∼150 bp) for C3 and C4 regions, suggesting binding by SOX9 to nucleosomal DNA”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSOX9 binding to closed chromatin, as in C2-C4, is not dictated by SOX motifs, but the ability of SOX9 to open chromatin, as in C2, is dependent on the presence of a SOX motif.
“This suggests SOX9 binding to closed chromatin, as in C2-C4, is not dictated by SOX motifs, but the ability of SOX9 to open chromatin, as in C2, is dependent on the presence of a SOX motif.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThese factors function upstream of SOX9 or parallel to SOX9, and SOX9 can initiate EndMT independently of these TFs.
“Our data may suggest that these factors function upstream of SOX9 or parallel to SOX9 and that SOX9 can initiate EndMT independently of these TFs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataH2A.Z enrichment and SOX motifs are prerequisites for silent chromatin regions to become opened and activated by SOX9.
“these are prerequisites for silent chromatin regions to become opened and activated by SOX9.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningH3S28P may weaken SOX9 binding and evict SOX9 from nucleosomes, contributing to dynamic SOX9 chromatin binding.
“H3S28P may weaken SOX9 binding and evict SOX9 from nucleosomes, contributing to the dynamic SOX9 chromatin binding.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAP-1 and ETS family TFs maintain active enhancers in HUVECs, and downregulation of these factors leads to loss of chromatin accessibility.
“suggesting that AP-1 and ETS family TFs maintain active enhancers in HUVECs, and downregulation of these factors leads to loss of chromatin accessibility.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe SOX dimer motif seems to work as an intrinsic signal to guide SOX9 pioneer activity, as pioneering events predominantly occurred at regions with SOX dimer motifs.
“The SOX dimer motif seems to work as an intrinsic signal to guide SOX9 pioneer activity, as pioneering events predominantly occurred at regions with SOX dimer motifs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAlthough H2A.Z enrichment was lower in C2 than active C1, the presence of H2A.Z in otherwise silent chromatin may be a determinant for SOX9 pioneering.
“Although we observed a lower enrichment of H2A.Z in C2 regions compared to the active C1 regions, the presence of H2A.Z in otherwise silent chromatin may be a determinant for SOX9 pioneering.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningA single transcription factor can induce major chromatin restructuring and cell fate decisions.
“The activation of these chromatin regions drives expression of mesenchymal genes, highlighting the ability of one single TF to induce major chromatin restructuring and cell fate decisions.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBecause SOX9 was not detected bound to closing regions, closing of chromatin is likely a downstream effect of SOX9 action, such as through downregulation of AP-1 and ETS family TFs.
“As we did not detect SOX9 bound to these regions, closing of chromatin is likely a downstream effect of SOX9 action, such as through the downregulation of AP-1 and ETS family TFs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataChromatin changes induced by SOX9 were stable and driving activation of mesenchymal genes and cell fate transition.
“The chromatin changes induced by SOX9 were, however, stable and driving activation of mesenchymal genes and cell fate transition.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSOX9 did not associate with chromatin marked with H3S28P in vivo, confirming that this modification may disrupt SOX9 chromatin binding.
“SOX9 did not associate with chromatin marked with H3S28P in vivo, confirming that this modification may disrupt SOX9 chromatin binding.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSOX9 binds silent chromatin either by transient scanning or by specific binding to regions containing a SOX dimer motif and an H2A.Z-containing nucleosome.
“To summarize, we propose a model for SOX9-induced EndMT whereby SOX9 binds silent chromatin either by transient scanning or by specific binding to regions containing a SOX dimer motif and an H2A.Z-containing nucleosome.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDynamic chromatin binding has been observed for other pioneer TFs.
“Dynamic chromatin binding has been observed for other pioneer TFs (47) and pioneering may be viewed as a one-time event, meaning that SOX9 does not need to remain bound at sites once opened.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Mayran, 2018, Pioneer factor pax7 deploys a stable enhancer repertoire for specification of cell fate, Nat. Genet. source
May combine two claims.
Interpretationown dataIn EndMT, SOX9 expression alone is sufficient for chromatin opening and cell fate transition.
“Nevertheless, we show that in EndMT, SOX9 expression alone is sufficient for chromatin opening and cell fate transition.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSOX9 may not be crucial for epigenetic changes during chondrogenesis.
“For instance, SOX9 may not be crucial for epigenetic changes during chondrogenesis (20).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Liu, 2018, SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis, Development source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTissue damage may stimulate EndMT to give rise to fibroblasts during wound healing or fibrotic diseases and EndMT forms cancer-associated fibroblasts in the tumor microenvironment, which regulates disease progression.
“Tissue damage may stimulate EndMT to give rise to fibroblasts during wound healing or fibrotic diseases and EndMT forms cancer-associated fibroblasts in the tumor microenvironment, which regulates disease progression (75).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [75] Lin, 2012, The role of endothelial-mesenchymal transition in development and pathological process, IUBMB Life source
May combine two claims.
Interpretationown dataIn most cases, following chromatin opening, SOX9 gets evicted from the nucleosomes, but the chromatin regions remain open and activate associated genes essential for the mesenchymal cell transition.
“In most cases, following chromatin opening, SOX9 gets evicted from the nucleosomes, possibly due to H3S28P enrichment, but the chromatin regions remain open and activate associated genes essential for the mesenchymal cell transition.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIn regions with a SOX dimer motif and an H2A.Z-containing nucleosome, SOX9 opens the local chromatin structure and enriches active histone modifications.
“In the latter regions, SOX9 opens the local chromatin structure and enriches active histone modifications.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe requirement for SOX9 in regulating the chromatin landscape may differ between cellular systems.
“The requirement for SOX9 in regulating the chromatin landscape may differ between cellular systems.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFollowing chromatin opening, H3S28 is phosphorylated and SOX9 is evicted from the site.
“suggesting that following chromatin opening, H3S28 is phosphorylated and SOX9 is evicted from the site.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The mechanisms by which SOX9 induces EndMT are not known.
“Although several lines of evidence indicate that SOX9 is essential for promoting a mesenchymal phenotype, the mechanisms of SOX9 in EndMT induction have not been evident.”
The paper relies on this without support.
The epigenetic requirements of SOX9 to alter chromatin and drive cell fate decisions remain uncertain and may vary between cell types.
“In summary, the epigenetic requirements of SOX9 to alter chromatin and drive cell fate decisions remains uncertain and may vary between cell types.”
The paper relies on this without support.
SOX9 expression in HUVECs is a valid model for EndMT in atherosclerosis.
“Possible role of SOX9 in chromatin opening in cells undergoing EndMT in atherosclerosis”
The paper relies on this without support.
The scRNA-seq data from atherosclerotic lesions accurately distinguish fibroblasts from endothelial cells.
“differentially expressed genes between fibroblasts and endothelial cells from the scRNA-seq data in atherosclerotic lesions”
The paper relies on this without support.
The scRNA-seq and scATAC-seq datasets from Andueza et al. can be co-embedded and their clusters compared to infer chromatin accessibility changes along EndMT.
“We co-embedded their scRNA-seq and scATAC-seq datasets and analysed differentially accessible regions in the clusters (Figure 8A).”
The paper relies on this without support.
Enrichment of SOX motifs in newly accessible chromatin regions indicates that SOX9 is the factor opening those regions in lesions.
“Interestingly, SOX motifs were significantly enriched in regions that became newly accessible in EC8 only (Figure 8C).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SOX9 is critical for AV valve development, including EndMT and matrix remodelling.
“SOX9 is critical for AV valve development, including in EndMT and matrix remodelling16,17,51,52”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [52]
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“Bigwig and bed files were analysed using IGV (36), Galaxy (37) and Cistrome (38).”
MethodMechanisms of hepatic fibrogenesis
Lee, U. E., & Friedman, S. L. (2011) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2011.02.005 · Cited by 923 · cited 1× · see citing works
“SOX9 can drive cancer invasion and metastasis in multiple cancers, including prostate, breast, colon, gastric, and lung (summarized in (13)) and is involved in promoting liver and cardiac fibrosis by stimulating ECM deposition (14,15).”
BackgroundTargeted in situ genome-wide profiling with high efficiency for low cell numbers
Skene, P. J., Henikoff, J. G., & Henikoff, S. (2018) · Nature Protocols · doi:10.1038/nprot.2018.015 · Cited by 803 · see citing works
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.017 · Cited by 780 · cited 2× · see citing works
“The pluripotency factors OCT4, SOX2, and KLF4, when acting as pioneer TFs, bind nucleosomes in vitro by targeting partial and degenerate DNA motifs displayed on the nucleosome surface (64).”
BackgroundCistrome: an integrative platform for transcriptional regulation studies
Liu, T., Ortiz, J. A., Taing, L., Meyer, C. A., Lee, B. T. K., Zhang, Y., Shin, H., Wong, S. S., Ma, J., Lei, Y., et al. (2011) · Genome biology · doi:10.1186/gb-2011-12-8-r83 · Cited by 705 · cited 2× · see citing works
“Heatmaps and average profile plots were generated in ChAsE and Cistrome.”
MethodEndothelial to Mesenchymal Transition in Cardiovascular Disease
Kovacic, J. C., Dimmeler, S., Harvey, R. P., Finkel, T., Aikawa, E. R., Krenning, G., & Baker, A. H. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.09.089 · Cited by 634 · cited 1× · see citing works
“In addition to being crucial for heart valve development, EndMT can be initiated in adults by tissue damage or inflammation and contribute to diseases such as atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis (48).”
BackgroundThe transcriptional control of trunk neural crest induction, survival, and delamination
Cheung, M., Chaboissier, M.-C., Mynett, A., Hirst, E., Schedl, A., & Briscoe, J. (2005) · Developmental Cell · doi:10.1016/j.devcel.2004.12.010 · Cited by 427 · see citing works
The roles of histone variants in fine-tuning chromatin organization and function
Martire, S., & Banaszynski, L. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0262-8 · Cited by 392 · cited 1× · see citing works
“Z has been shown to destabilize nucleosomes and is often found at active promoters and enhancers (71), which we observed in our C1 cluster.”
BackgroundDefinition of a consensus DNA binding site for SRY
Harley, V. R., Lovell-Badge, R. H., & Goodfellow, P. N. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.8.1500 · Cited by 386 · cited 1× · see citing works
“The HMG domain was first identified in SRY, a crucial factor for mammalian sex determination (2,3).”
BackgroundPioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice
Adam, R. C., Yang, H., Rockowitz, S., Larsen, S. B., Nikolova, M., Oristian, D., Polak, L., Kadaja, M., Asare, A., Zheng, D., et al. (2015) · Nature · doi:10.1038/nature14289 · Cited by 376 · see citing works
Slug is a direct Notch target required for initiation of cardiac cushion cellularization
Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200710067 · Cited by 363 · cited 1× · see citing works
“Interestingly, both SNAI1 and SNAI2 are required for EndMT in cardiac cushion morphogenesis in mice (67).”
BackgroundSelf-citationEndothelial TGF-β signalling drives vascular inflammation and atherosclerosis
Chen, P., Qin, L., Li, G., Wang, Z., Dahlman, J. E., Malagon-Lopez, J., Gujja, S., Cilfone, N. A., Kauffman, K. J., Sun, L., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0102-3 · Cited by 348 · see citing works
Cell fate control by pioneer transcription factors
Iwafuchi-Doi, M., & Zaret, K. S. (2016) · Development · doi:10.1242/dev.133900 · Cited by 304 · see citing works
Noseda, M., McLean, G. W., Niessen, K. S., Chang, L., Pollet, I. L., Montpetit, R., Shahidi, R., Dorovini‐Zis, K., Li, L., Beckstead, B. L., et al. (2004) · Circulation Research · doi:10.1161/01.res.0000124300.76171.c9 · Cited by 294 · see citing works
Self-citationEssential role of Sox9 in the pathway that controls formation of cardiac valves and septa
Akiyama, H., Chaboissier, M.-C., Behringer, R. R., Rowitch, D. H., Schedl, A., Epstein, J. A., & de Crombrugghe, B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401711101 · Cited by 265 · cited 2× · see citing works
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
BackgroundAndueza, A., Kumar, S., Kim, J. Y., Kang, D. W., Mumme, H., Perez, J. I., Villa-Roel, N., & Jo, H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108491 · Cited by 243 · cited 5× · see citing works
“generated a pseudotime trajectory which indicated EC8 consisted of cells undergoing EndMT, expressing both endothelial and mesenchymal marker genes in response to chronic disturbed flow, while EC6 represented an earlier intermediate endothelial phenotype, with the Fibro and SMC clusters as the terminally differentiate…”
BackgroundMethodInfluentialLincoln, J., Kist, R., Scherer, G., & Yutzey, K. E. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.02.002 · Cited by 187 · see citing works
Ets1 and ets2 are required for endothelial cell survival during embryonic angiogenesis
Wei, G., Srinivasan, R., Cantemir-Stone, C. Z., Sharma, S. M., Santhanam, R., Weinstein, M., Muthusamy, N., Man, A. K., Oshima, R. G., Leone, G., et al. (2009) · Blood · doi:10.1182/blood-2009-03-211391 · Cited by 185 · cited 2× · see citing works
“Genes possibly repressed by SOX9 include endothelial markers, such as VWF and PECAM1, as well as genes encoding TFs important for endothelial cell functions, including ERG (60) and ETS2 (61).”
BackgroundDistinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte
Ohba, S., He, X., Hojo, H., & McMahon, A. P. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.013 · Cited by 179 · cited 3× · see citing works
“Searching for enriched DNA binding motifs in the SOX9 peaks, we identified SOX motifs as the top three enriched (Supplementary Figure S3E), including two dimer (one defined and one more degenerate) and one monomer SOX motif, which are similar to previously identified motifs for SOX9 (5,17,53,62).”
BackgroundResultThe role of endothelial-mesenchymal transition in development and pathological process
Lin, F., Wang, N., & Zhang, T. (2012) · IUBMB Life · doi:10.1002/iub.1059 · Cited by 177 · cited 1× · see citing works
“Tissue damage may stimulate EndMT to give rise to fibroblasts during wound healing or fibrotic diseases and EndMT forms cancer-associated fibroblasts in the tumor microenvironment, which regulates disease progression (75).”
BackgroundPeirano, R. I. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.16.3047 · Cited by 175 · cited 1× · see citing works
“SOXE factors (SOX8, SOX9 and SOX10) also possess a dimerization domain upstream of the HMG domain that mediates DNA-dependent dimerization to a palindromic ACAAa/tGnnnnCa/tTTGT DNA sequence (4,5).”
BackgroundPioneer factor pax7 deploys a stable enhancer repertoire for specification of cell fate
Mayran, A., Khetchoumian, K., Hariri, F., Pastinen, T., Gauthier, Y., Balsalobre, A., & Drouin, J. (2018) · Nature Genetics · doi:10.1038/s41588-017-0035-2 · Cited by 171 · see citing works
Takaku, M., Grimm, S. A., Shimbo, T., Perera, L., Menafra, R., Stunnenberg, H. G., Archer, T. K., Machida, S., Kurumizaka, H., & Wade, P. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0897-0 · Cited by 151 · see citing works
Sock, E. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg158 · Cited by 142 · cited 1× · see citing works
“Mutations in and around the SOX9 gene, some that specifically disrupt dimerization, are known to cause Campomelic Dysplasia (CD), a skeletal dysmorphology syndrome characterized by bowing of the limb long bones, male-to-female sex reversal and a variety of congenital heart defects (6,7).”
BackgroundLu, M.-F., Cheng, H.-T., Kern, M. J., Potter, S. S., Tran, B., G. H. Diekwisch, T., & F. Martin, J. (1999) · Development · doi:10.1242/dev.126.3.495 · Cited by 136 · see citing works
Pioneer Factor-Nucleosome Binding Events during Differentiation Are Motif Encoded
Meers, M. P., Janssens, D. H., & Henikoff, S. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.025 · Cited by 135 · see citing works
Kalna, V., Yang, Y., Peghaire, C. R., Frudd, K., Hannah, R., Shah, A. V., Osuna Almagro, L., Boyle, J. J., Göttgens, B., Ferrer, J., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.313788 · Cited by 119 · cited 9× · see citing works
“Regions with decreased chromatin accessibility were enriched for motifs for AP-1 family of TFs, such as JUN and FOS, as well as motifs for the endothelial TFs ETS and ERG (Supplementary Figure S5D).”
BackgroundInfluentialEctopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis
Hanley, K. P., Oakley, F., Sugden, S. A., Wilson, D. I., Mann, D. A., & Hanley, N. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707390200 · Cited by 117 · cited 1× · see citing works
“cellular matrix (ECM) production and organization (8,9).”
Molecular basis for the genome engagement by Sox proteins
Hou, L., Srivastava, Y., & Jauch, R. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.005 · Cited by 113 · cited 1× · see citing works
“Around 20 SOX transcription factors (TFs) with divergent developmental functions have been identified, of which many act as master regulators that control critical transcriptional programs to determine cell fate and differentiation (1).”
BackgroundReichert, M., Takano, S., von Burstin, J., Kim, S.-B., Lee, J.-S., Ihida-Stansbury, K., Hahn, C., Heeg, S., Schneider, G., Rhim, A. D., et al. (2013) · Genes & Development · doi:10.1101/gad.204453.112 · Cited by 112 · cited 1× · see citing works
“Other upregulated target genes include the Homeobox TF genes PRRX1 and PKNOX2, both of which have roles in mesenchyme development (56,57), while PRRX1 also promotes EMT in cancers (58,59).”
BackgroundTomo-Seq identifies SOX9 as a key regulator of cardiac fibrosis during ischemic injury
Lacraz, G. P. A., Junker, J. P., Gladka, M. M., Molenaar, B., Scholman, K. T., Vigil-Garcia, M., Versteeg, D., de Ruiter, H., Vermunt, M. W., Creyghton, M. P., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.027832 · Cited by 111 · cited 1× · see citing works
“SOX9 can drive cancer invasion and metastasis in multiple cancers, including prostate, breast, colon, gastric, and lung (summarized in (13)) and is involved in promoting liver and cardiac fibrosis by stimulating ECM deposition (14,15).”
BackgroundH2A.Z: a molecular rheostat for transcriptional control
Subramanian, V., Fields, P. A., & Boyer, L. A. (2015) · F1000Prime Reports · doi:10.12703/p7-01 · Cited by 102 · cited 1× · see citing works
“Z occupancy seems to correlate with pioneer TF binding to nucleosome-occupied regions and has been suggested to act as a scaffold for binding of pioneer TFs and chromatin remodelers (72,73).”
BackgroundOh, C.-D., Lu, Y., Liang, S., Mori-Akiyama, Y., Chen, D., de Crombrugghe, B., & Yasuda, H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107577 · Cited by 101 · cited 2× · see citing works
“Searching for enriched DNA binding motifs in the SOX9 peaks, we identified SOX motifs as the top three enriched (Supplementary Figure S3E), including two dimer (one defined and one more degenerate) and one monomer SOX motif, which are similar to previously identified motifs for SOX9 (5,17,53,62).”
BackgroundResultSOX9 stem-cell factor: clinical and functional relevance in cancer
Aguilar-Medina, M., Avendaño-Félix, M., Lizárraga-Verdugo, E., Bermúdez, M., Romero-Quintana, J. G., Ramos-Payan, R., Ruíz-García, E., & López-Camarillo, C. (2019) · Journal of Oncology · doi:10.1155/2019/6754040 · Cited by 97 · cited 1× · see citing works
“SOX9 can drive cancer invasion and metastasis in multiple cancers, including prostate, breast, colon, gastric, and lung (summarized in (13)) and is involved in promoting liver and cardiac fibrosis by stimulating ECM deposition (14,15).”
BackgroundTakahashi, Y., Sawada, G., Kurashige, J., Uchi, R., Matsumura, T., Ueo, H., Takano, Y., Akiyoshi, S., Eguchi, H., Sudo, T., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.339 · Cited by 92 · cited 1× · see citing works
“Other upregulated target genes include the Homeobox TF genes PRRX1 and PKNOX2, both of which have roles in mesenchyme development (56,57), while PRRX1 also promotes EMT in cancers (58,59).”
BackgroundHuang, Y.-H., Jankowski, A., Cheah, K. S. E., Prabhakar, S., & Jauch, R. (2015) · Scientific Reports · doi:10.1038/srep10398 · Cited by 86 · see citing works
Hino, K., Saito, A., Kido, M., Kanemoto, S., Asada, R., Takai, T., Cui, M., Cui, X., & Imaizumi, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.543322 · Cited by 84 · cited 1× · see citing works
“Among the upregulated genes were previously characterized SOX9 target genes, such as ECM genes encoding collagens IX and XI (53), as well as other TF genes like SOX5, SOX6, CREB3L2, and NFIA, highlighting the role of SOX9 as a master regulator (17,54,55).”
BackgroundJosefowicz, S. Z., Shimada, M., Armache, A., Li, C. H., Miller, R. M., Lin, S., Yang, A., Dill, B. D., Molina, H., Park, H.-S., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.09.026 · Cited by 84 · cited 1× · see citing works
“This suggests that H3S28P, which is associated with open chromatin and activation of transcription (65), may evict SOX9 from nucleosomes following chromatin opening and activation.”
BackgroundThe mechanistic basis for chromatin regulation by pioneer transcription factors
Iwafuchi‐Doi, M. (2019) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1427 · Cited by 82 · see citing works
Liu, C.-F., Angelozzi, M., Haseeb, A., & Lefebvre, V. (2018) · Development · doi:10.1242/dev.164459 · Cited by 73 · cited 2× · see citing works
“For instance, SOX9 may not be crucial for epigenetic changes during chondrogenesis (20).”
BackgroundHigh glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell
Yu, C.-H., Suriguga, S., Gong, M., Liu, W., Cui, N.-X., Wang, Y., Du, X., & Yi, Z.-C. (2017) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2017.03.007 · Cited by 72 · see citing works
Chromatin scanning by dynamic binding of pioneer factors
Zaret, K. S., Lerner, J., & Iwafuchi-Doi, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.024 · Cited by 68 · cited 1× · see citing works
“Notably, we did not identify significant biological processes associated with the regions in C4, although this was the largest of the four clusters, suggesting that this cluster represents non-specific binding or scanning by SOX9 (63).”
BackgroundThe conserved sex regulator DMRT1 recruits SOX9 in sexual cell fate reprogramming
Lindeman, R. E., Murphy, M. W., Agrimson, K. S., Gewiss, R. L., Bardwell, V. J., Gearhart, M. D., & Zarkower, D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab448 · Cited by 66 · cited 1× · see citing works
“In gonadal cell fate transition, DMRT1 was shown to open chromatin to allow binding of SOX9, while SOX9 did not have strong pioneering abilities (74).”
BackgroundSOX9 modulates the expression of key transcription factors required for heart valve development
Garside, V. C., Cullum, R., Alder, O., Lu, D. Y., Vander Werff, R., Bilenky, M., Zhao, Y., Jones, S. J. M., Marra, M. A., Underhill, T. M., et al. (2015) · Development · doi:10.1242/dev.125252 · Cited by 65 · cited 6× · see citing works
“During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and where SOX9 activates transcription of key regulators of heart valve development (11,17).”
BackgroundResultInfluentialSelf-citationZhao, J., Patel, J., Kaur, S., Sim, S.-L., Wong, H. Y., Styke, C., Hogan, I., Kahler, S., Hamilton, H., Wadlow, R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22717-9 · Cited by 63 · cited 2× · see citing works
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
BackgroundChAsE: chromatin analysis and exploration tool
Younesy, H., Nielsen, C. B., Lorincz, M. C., Jones, S. J. M., Karimi, M. M., & Möller, T. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw382 · Cited by 41 · see citing works
Coustry, F., Oh, C.-D., Hattori, T., Maity, S. N., de Crombrugghe, B., & Yasuda, H. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq417 · Cited by 37 · cited 3× · see citing works
“SOX9 remodeled chromatin and activated transcription at this site on an in vitro assembled chromatin template (18).”
BackgroundResultInfluentialFuglerud, B. M., Lemma, R. B., Wanichawan, P., Sundaram, A. Y. M., Eskeland, R., & Gabrielsen, O. S. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx364 · Cited by 36 · cited 1× · see citing works
“Our results suggests that SOX9 harbours this ability but, as observed with other pioneer TFs (47,69,70), not all SOX9 binding events result in opening of chromatin.”
ResultSelf-citationChang, A. C. Y., Garside, V. C., Fournier, M., Smrz, J., Vrljicak, P., Umlandt, P., Fuller, M., Robertson, G., Zhao, Y., Tam, A., et al. (2014) · Developmental Dynamics · doi:10.1002/dvdy.24127 · Cited by 35 · cited 1× · see citing works
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
BackgroundSelf-citationCheung, K., Barter, M. J., Falk, J., Proctor, C. J., Reynard, L. N., & Young, D. A. (2020) · The FASEB Journal · doi:10.1096/fj.201902061rr · Cited by 23 · cited 1× · see citing works
“In chondrogenic systems, SOX9 can activate enhancers (19), but may not be required for the initiation of chromatin changes (20).”
Liguori, T. T. A., Liguori, G. R., Moreira, L. F. P., & Harmsen, M. C. (2019) · Cell Proliferation · doi:10.1111/cpr.12629 · Cited by 17 · see citing works
Zhou, W., Zhu, H., Zhao, J., Li, H., Wan, Y., Cao, J., Zhao, H., Yu, J., Zhou, R., Yao, Y., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064237 · Cited by 13 · cited 1× · see citing works
“Other upregulated target genes include the Homeobox TF genes PRRX1 and PKNOX2, both of which have roles in mesenchyme development (56,57), while PRRX1 also promotes EMT in cancers (58,59).”
BackgroundCauchy, P., Koch, F., & Andrau, J.-C. (2017) · Transcription · doi:10.1080/21541264.2017.1291395 · Cited by 10 · see citing works
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Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application
Chen, Y., Liang, R., Li, Y., Jiang, L., Ma, D., Luo, Q., & Song, G. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02030-9 · Cited by 174 · see citing works
“98 Research also revealed that FoxA2 binding alone did not increase the permissive of chromatin.”
SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys
Aggarwal, S., Wang, Z., Pacheco, D. R. F., Rinaldi, A., Rajewski, A. C., Callemeyn, J., Loon, E. V., Lamarthée, B., Covarrubias, A. E., Hou, J., et al. (2024) · Science · doi:10.1126/science.add6371 · Cited by 136 · see citing works
Pioneer factors: roles and their regulation in development
Barral, A., & Zaret, K. S. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.10.007 · Cited by 126 · see citing works
The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates
Yang, Y., Gomez, N. C., Infarinato, N. R., Adam, R. C., Sribour, M., Baek, I., Laurin, M., & Fuchs, E. V. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01184-y · Cited by 74 · see citing works
A review of recent studies on the pathogenesis of Systemic Sclerosis: focus on fibrosis pathways
Jiménez, S. A., Mendoza, F. A., & Piera-Velázquez, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1551911 · Cited by 34 · see citing works
Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Katsuda, T., Sussman, J. H., Ito, K., Katznelson, A., Yuan, S., Takenaka, N., Li, J., Merrell, A. J., Cure, H., Li, Q., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45939-z · Cited by 33 · see citing works
Khalid, S., Ekram, S., Ramzan, F., et al. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1127303 · Cited by 18 · see citing works
“Being the master regulator of chondrocytes (57), it works efficiently with downstream and upstream of the other regulators and potentially hit the expression of aggrecan and colII (58).”
BackgroundPre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development
Darbellay, F., Ramisch, A., Lopez‐Delisle, L., Kosicki, M., Rauseo, A., Jouini, Z., Visel, A., & Andrey, G. (2024) · Nature Communications · doi:10.1038/s41467-024-49203-2 · Cited by 16 · see citing works
“In fact, SOX9 as well asseveral FOX genes transcription factors have been shown to act as pioneer factors in different biological context and could therefore indeed act early on to open and prime chondrogenic enhancers for activity 61,62 .”
Cell diversity and plasticity during atrioventricular heart valve EMTs
Lotto, J., Cullum, R., Drissler, S., Arostegui, M., Garside, V. C., Fuglerud, B. M., Clement-Ranney, M., Thakur, A., Underhill, T. M., & Hoodless, P. A. (2023) · Nature Communications · doi:10.1038/s41467-023-41279-6 · Cited by 13 · see citing works
Self-citationThe gene regulatory landscape driving mouse gonadal supporting cell differentiation
Stévant, I., Abberbock, E., Ridnik, M., Weiss, R., Swisa, L., Futtner, C. R., Maatouk, D. M., Lovell-Badge, R. H., Malysheva, V., & Gonen, N. (2025) · Science Advances · doi:10.1126/sciadv.adv1885 · Cited by 12 · see citing works
“SOX9 has been described as being a pioneer TF that is able to bind closed chromatin, inducing cis-regulatory element opening that leads to cell reprogramming in embryonic epidermal stem cells and umbilical vein endothelial cells ( 87 , 88 ).”
Halblander, F. N., Meng, F. W., & Murphy, P. J. (2023) · Developmental Biology · doi:10.1016/j.ydbio.2023.12.010 · Cited by 8 · see citing works
A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development
Abberbock, E., Ridnik, M., Stévant, I., Weiss, R., Bamberger, C., Lhermann, S. Z., Lubman, M., Yao, Y.-M.-M.-Y., Afek, A., Poulat, F., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71328-9 · Cited by 7 · see citing works
Cellular Transdifferentiation: A Crucial Mechanism of Fibrosis in Systemic Sclerosis
Jiménez, S. A., & Piera-Velázquez, S. (2023) · Current Rheumatology Reviews · doi:10.2174/0115733971261932231025045400 · Cited by 7 · see citing works
Pioneer factors outline chromatin architecture
Gómora‐García, J. C., & Furlan-Magaril, M. (2025) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2025.102480 · Cited by 6 · see citing works
Nuclear mechanosensing of the aortic endothelium in health and disease
Mannion, A. J., & Holmgren, L. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.050361 · Cited by 6 · see citing works
Vance, M. L., Nagy, D., Brunner, E., Morkotinis, V., Black, J. L., Refai, L. H., Csiszár, A., & Conley, S. M. (2025) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2025.103747 · Cited by 5 · see citing works
“32,118,138,157,160,161 Many of these studies used unbiased genetic approaches to detect transcriptional regulators across a multitude of tissue types and disease models, suggesting that the regulation of EndMT may vary across different tissues and stimuli.”
The Ets2 super-enhancer modulates endothelial-mesenchymal transition during cardiac ageing
Guo, Z., Li, L., Luo, J., Xue, W., Bian, S., Zhu, Y., Huo, D., Yang, W., Ma, J., Hao, Y., et al. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf242 · Cited by 5 · see citing works
Tang, H., Zhong, J.-Y., Yu, X., Chai, H., Liu, R., & Zeng, T. (2024) · iScience · doi:10.1016/j.isci.2024.111131 · Cited by 5 · see citing works
Wei, F., Yan, Y., Liu, G., Peng, B., Liu, Y., & Chen, Q. (2023) · PeerJ · doi:10.7717/peerj.16306 · Cited by 4 · see citing works
“…the transcription factor SOX9 is activated at the onset of endothelial-to-mesenchymal transition, which displays features of a pioneer transcription factor, such as opening of chromatin and leading to deposition of active histone modi fi cations at silent chromatin regions ( Fuglerud et al., 2022 ).”
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- Authors
- Fuglerud, B. M., Drissler, S., Lotto, J., Stephan, T. L., Thakur, A., Cullum, R., & Hoodless, P. A.
- Affiliations
- BC Cancer Agency (CA)
- Corresponding author
- Hoodless, Pamela A
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-07-29
- Volume
- 50
- Issue
- 15
- Pages
- 8547-8565
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC9410909
- OpenAlex
- W4288708930
- Cited by
- 35
- References
- 77
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 6 · 2023: 9 · 2022: 1
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Funders
- Research Council of Norway FRIPRO Mobility Research (275783)
- Canadian Institutes for Health Research (159512)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- SOX9, endothelial-to-mesenchymal transition, chromatin accessibility, pioneer transcription factors, histone modifications, H2A.Z, histone phosphorylation, single-cell chromatin accessibility, atherosclerosis, human umbilical vein endothelial cells, transcriptional reprogramming
- MeSH terms
- Chromatin, Gene Expression Regulation, Humans, Signal Transduction, SOX9 Transcription Factor, Human Umbilical Vein Endothelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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