HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements
Open accessAbstract
Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers. In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner. How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown. Using analysis of genome-wide histone modifications, TF binding, chromatin accessibility and gene expression, we show that HNF4A is essential for an active chromatin state. Using HNF4A loss and gain of function experiments in vivo and in cell lines in vitro, we show that HNF4A affects H3K4me1, H3K27ac and chromatin accessibility, highlighting its contribution to the establishment and maintenance of a transcriptionally permissive epigenetic state. Mechanistically, HNF4A interacts with the mixed-lineage leukaemia 4 (MLL4) complex facilitating recruitment to HNF4A-bound regions. Our findings indicate that HNF4A enriches H3K4me1, H3K27ac and establishes chromatin opening at transcriptional regulatory regions.
AI snapshot
Written from the paper’s full text.
TL;DR
HNF4A is required to maintain H3K4me1, H3K27ac, and chromatin accessibility at its bound regulatory regions in adult mouse liver, and ectopic HNF4A can establish these active enhancer features in fibroblasts. Mechanistically, HNF4A physically interacts with the MLL4 complex and recruits it to HNF4A-bound regions to deposit H3K4me1 and promote gene expression.
Key findings
- In adult mouse liver, hepatocyte-specific Hnf4a deletion reduced H3K4me1, H3K27ac, and chromatin accessibility at HNF4A-bound regions (HBRs), with HBR-associated genes expressed at significantly lower levels in cKO livers (t test, p < 0.0001; n = 3 biologically independent samples).
- Ectopic HNF4A expression in NIH 3T3 fibroblasts caused a mesenchymal-to-epithelial shift, 5349 differentially expressed genes (2668 upregulated, 2681 downregulated), and increased global H3K4me1 by ~23% and H3K27ac by ~59%; 4083 HNF4A-bound regions were identified, including 942 newly activated C1 regions.
- HNF4A co-immunoprecipitated with MLL4 complex proteins ASH2L, RBBP5, and UTX, and proximity ligation assays confirmed HNF4A–MLL4 and HNF4A–ASH2L interactions; MLL4 or UTX shRNA knockdown significantly reduced HNF4A-induced H3K4me1 and expression of Apoc2 and Aqp1.
- FOXA factors were not globally required for H3K4me1/H3K27ac maintenance at HBRs: in FOXA triple-knockout livers, no global effect on these histone modifications was observed at HBRs, whereas HNF4A loss reduced them.
Methods
- Adult mouse liver model: tamoxifen-inducible, Albumin promoter-driven Cre (Alb-CreERT2) crossed with Hnf4afl/fl mice to generate hepatocyte-specific Hnf4a cKO; controls were Hnf4afl/fl, Cre-negative with no tamoxifen.
- Cell models: NIH 3T3 fibroblasts transduced with mouse Hnf4a-IRES-eGFP or empty vector; HEK293T and HepG2 cells used for validation; assays included ChIP-seq, CUT&Tag, ATAC-seq, RNA-seq, RT-qPCR, western blot, co-immunoprecipitation, proximity ligation assay, and shRNA knockdown.
- Sequencing reads mapped to mm10; peaks called with MACS2; analyses used Cistrome, Galaxy, IGV, GREAT, ChAsE clustering, and motif analysis; RNA-seq used STAR and Cufflinks; statistical significance assessed by Student’s t test.
Limitations
- The paper states that correlating single genes to specific enhancers is difficult because enhancer-to-gene mapping is often inaccurate and most genes are regulated by multiple enhancers with redundancy; it also notes that the adult liver deletion and 3T3 ectopic expression systems differ fundamentally, producing distinct HNF4A-bound regions and gene regulation, so overall genomic patterns may not generalize to all genes.
- The paper states that ChIP-seq, CUT&Tag, and ATAC-seq were each completed only once, although qPCR was used for validation (not shown); RNA-seq was done on 3 biological replicates, and ChIP-qPCR used n = 2 technical replicates.
- Evident from the text: mechanistic conclusions rely substantially on overexpression in 3T3/HEK293T cells and shRNA knockdown, with limited in vivo rescue or timed chromatin-opening experiments; the authors note that further investigation with well-timed experiments is needed to define factors required for chromatin opening.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
58 of 66 cited sources checked · 28 supported · 1 flagged · accuracy not yet measured
- Findingown data
In contrast to the Hnf4a cKO, there is no global effect on histone modifications between control and FTKO livers at HBRs.
“In contrast to the Hnf4a cKO, we observed no global effect on histone modifications between control and FTKO livers at HBRs (Supplementary Fig. 2b–d).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [52] Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020). source
The Results section on FoxA and enhancer activity reports substantial changes in histone marks at FoxA/HNF4α-cobound sites in triple-null livers, contrary to an unqualified claim of no effect at HNF4α-binding regions. Its analysis is limited to cobound sites and does not establish a global result across all HBRs; the paper also does not report the cited sentence’s histone-modification comparison with Hnf4a cKO. (LLM, conf=0.76)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Findingown data
HNF4A depletion in adult mouse liver reduces H3K4me1 at locations normally occupied by HNF4A.
“In agreement with recent papers50,53, we observed reduced levels of H3K4me1 in cKO livers at locations normally occupied by HNF4A (Fig. 1b).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [50] Qu, M., Qu, H., Jia, Z. & Kay, S. A. HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape. Nat. Commun. 12, 6350 (2021). source
- cites [53] Hunter, A. L. et al. HNF4A modulates glucocorticoid action in the liver. Cell Rep. 39, 110697 (2022). source
The Results section on chromatin accessibility reports that HNF4A loss reduces accessibility at sites usually marked by HNF4A. The Results section on chromatin state reports H3K4me1 levels at GR sites in normal liver, but does not show that H3K4me1 decreases after HNF4A depletion. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
95% of our ~12,000 HBRs matched regions identified as bound by HNF4A in Reizel et al. data.
“we compared the adult mouse liver HNF4A ChIP-seq data from Reizel et al.52 to our HNF4A ChIP-seq data48,49 and observed that 95% of our ~12,000 HBRs matched regions identified as bound by HNF4A in their data (Supplementary Fig. 1d).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [52] Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020). source
- cites [48] Thakur, A. et al. Hepatocyte nuclear factor 4-alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019). source
- cites [49] Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–71 (2014). source
- Premisecitation
HNF4A is required for active histone and DNA signatures at enhancers.
“While we previously showed that HNF4A is required for active histone and DNA signatures at enhancers48, its involvement in establishing the primed state that is laid down prior to activation was not examined.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [48] Thakur, A. et al. Hepatocyte nuclear factor 4-alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019). source
- Interpretationown data
FOXA factors are not always required for accessibility at HBRs.
“Furthermore, although FOXA factors act as pioneer factors in hepatocytes51,52, we show that FOXA factors are not always required for accessibility at HBRs.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [51] Iwafuchi-Doi, M. et al. The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Mol. Cell 62, 79–91 (2016). source
- cites [52] Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020). source
- Findingown data
H3K4me1 and H3K27ac were also reduced in Hnf4a cKO liver at the extended set of HBRs identified by Reizel et al.
“While the Reizel dataset identified many additional HNF4A bound regions (over 36,000 total regions), we found H3K4me1 and H3K27ac were also reduced in Hnf4a cKO liver at this extended set of HBRs (Supplementary Fig. 1e).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [52] Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020). source
The Methods (ChIP-seq; page unavailable) confirm that Reizel et al. generated a dataset of HNF4α-binding regions, supporting its use as the identified set of HBRs. Our copy does not verify the stated total of over 36,000 regions. The reduction of H3K4me1 and H3K27ac in Hnf4a cKO liver is explicitly presented as the citing authors’ own finding, not as Reizel et al.’s result. (LLM, conf=0.81)
Experimental — accuracy not yet measured
- Interpretationreasoning
Without HNF4A, nucleosome positioning is disrupted.
“This suggests that without HNF4A, the nucleosome positioning is disrupted, which may be a result of the fact that the loss of H3K4me1 reduces H3 eviction from the region34.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] Kang, Y., Kim, Y. W., Kang, J. & Kim, A. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers. Faseb j. 35, e21781 (2021). source
The genome-wide analysis reports that loss of H3K4me1 reduced histone H3 depletion at putative enhancers, supporting the cited sentence’s proposed mechanism. But the paper examines MLL3/4-altered K562 cells, not loss of HNF4A, and does not establish that nucleosome positioning is disrupted without HNF4A. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
HNF4A bound regions (HBRs) are flanked by nucleosomes marked with H3K4me1.
“HNF4A bound regions (HBRs) are flanked by nucleosomes marked with H3K4me148–50, leading us to question whether HNF4A contributes to the establishment and maintenance of H3K4me1 at HBRs.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [48] Thakur, A. et al. Hepatocyte nuclear factor 4-alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019). source
- cites [49] Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–71 (2014). source
The Results section (“Differentiation-Dependent Binding Sites Function as Temporal Enhancers”; page not provided) reports H3K4me1 enrichment on both sides of HNF4A/FOXA2 binding sites that remained occupied or were occupied in adult liver. It does not establish this pattern for all HNF4A-bound regions: sites bound only in the embryo instead showed a central H3K4me1 signal. The passage describes histone-mark signal, not nucleosomes directly. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [50] Qu, M., Qu, H., Jia, Z. & Kay, S. A. HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape. Nat. Commun. 12, 6350 (2021). source
The Results section on Hnf4a knockout reports H3K4me1 at HNF4A-binding sites and reduced H3K4me1 there after knockout. The paper does not establish the more specific claim that HNF4A-bound regions are flanked by H3K4me1-marked nucleosomes. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
In mouse livers depleted for FOXAs, a subset of regions where HNF4A and FOXA normally co-bind lose HNF4A binding.
“Using mouse livers depleted for FOXAs, a subset of regions was identified where HNF4A and FOXA normally co-bound but HNF4A binding was also lost with loss of FOXAs52.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [52] Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020). source
- Premisecitation
HNF4A interacts with TET proteins to maintain hydroxymethylation, an active DNA modification at enhancers.
“Previously, we determined that HNF4A interacts with TET proteins to maintain hydroxymethylation, an active DNA modification at enhancers48.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] Thakur, A. et al. Hepatocyte nuclear factor 4-alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019). source
- Premisecitation
HNF4A is unable to bind nucleosomes.
“While HNF4A can efficiently affect H3K4me1 and H3K27ac levels, it has been shown that HNF4A is unable to bind nucleosomes71, a defining feature of pioneer factors.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [71] Lerner, J. et al. Two-parameter mobility assessments discriminate diverse regulatory factor behaviors in chromatin. Mol. Cell 79, 677–688.e6 (2020). source
The Results section, “Nucleosome affinity of transcription factors predicts their chromatin mobility” (page unavailable), says HNF4A has “virtually no affinity for nucleosomes.” That supports very weak binding, but not the categorical claim that HNF4A is unable to bind them. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Findingown data
All regions with HNF4A bound (Set1 and Set2) are active regulatory elements with high H3K4me1, H3K27ac, and accessibility.
“All regions with HNF4A bound (Set1 and Set2) were identified as active regulatory elements with high H3K4me1, H3K27ac, and accessibility (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
HNF4A depletion reduces H3K27ac at HBRs genome-wide.
“CUT&Tag on control and cKO livers identified changes on a genome-wide scale and showed reduction of H3K27ac at HBRs (Fig. 1b).”
Quote in the paperNot a substantial claim - Findingown data
Little H3K4me1 and H3K27ac were observed at Set3, where only FOXA2 is bound.
“In contrast, little H3K4me1 and H3K27ac were observed at Set3, where only FOXA2 is bound.”
Quote in the paperSubstantial claim - Findingown data
Loss of HNF4A causes a shift in positioning of H3K4me1-marked nucleosomes that normally flank an HBR.
“the composite profile plot of H3K4me1 ChIP-seq data shows higher H3K4me1 flanking HBRs in control livers but peaks centered at what would be the HBRs in cKO livers (Fig. 1b), indicating a shift in the positioning of the H3K4me1 marked nucleosomes that normally flank an HBR.”
Quote in the paperSubstantial claim - Findingown data
Expression of genes associated with HBRs was decreased more in Set1 and Set2 than in Set3.
“Expression of genes associated with HBRs was decreased more in Set1 and Set2 than in Set3 (Supplementary Fig. 2a).”
Quote in the paperNot a substantial claim - Findingown data
Motif analysis showed HNF4A as the most significantly enriched motif in C1 regions.
“motif analysis showed HNF4A as the most significantly enriched (Fig. 4f).”
Quote in the paperSubstantial claim - Findingown data
H3K27ac increased ~59% alongside H3K4me1 in cells expressing HNF4A.
“We examined levels of other histone modifications by western blotting and found H3K27ac increased (~59%) alongside H3K4me1 in cells expressing HNF4A (Fig. 4b).”
Quote in the paperNot a substantial claim - Findingown data
Only 839 regions (20.5% of regions bound in HNF4A expressing 3T3s) were represented in both the HNF4A-expressing 3T3 and adult liver HBR datasets.
“Comparison of the HBRs in the expression system to the adult liver found only 839 regions (20.5% of regions bound in HNF4A expressing 3T3s) represented in both datasets (Supplementary Fig. 4b) although HNF4A binding motifs were similar (Supplementary Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
Regions with only HNF4A bound (Set1) showed reduction in both histone modifications and chromatin accessibility in the Hnf4a cKO liver.
“Interestingly, the regions with only HNF4A bound (Set1) showed reduction in both histone modifications and chromatin accessibility in the Hnf4a cKO liver (Fig. 2a, b) as well as a shift in H3K4me1 profile from nucleosomes flanking the HBR to nucleosomes present at the HBR (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Other histone modifications did not change significantly in HNF4A EE cells.
“Other histone modifications did not change significantly.”
Quote in the paperNot a substantial claim - Findingown data
HNF4A depletion modestly reduces chromatin accessibility at HBRs.
“Similarly, chromatin accessibility was modestly reduced at HBRs after deletion of Hnf4a (Fig. 1a, b).”
Quote in the paperNot a substantial claim - Findingown data
The common 839 regions are associated with genes enriched for metabolic processes.
“These common 839 regions are associated with genes enriched for metabolic processes (Supplementary Fig. 4d).”
Quote in the paperNot a substantial claim - Findingown data
Ectopic expression of HNF4A in 3T3 cells changes cell morphology from elongated spindle shape to cobblestone-like shape.
“Importantly, the cells changed from their original elongated spindle shape, typical of mesenchymal cells, to the cobblestone-like shape, characteristic of epithelial cells (Fig. 3d).”
Quote in the paperNot a substantial claim - Findingown data
Genes with an associated HBR are expressed at significantly lower levels in Hnf4a cKO livers compared to control.
“RNA-seq (see Supplementary Data 1 for full dataset) on control and Hnf4a cKO livers established that genes with an associated HBR were expressed at significantly lower levels in Hnf4a cKO livers (Fig. 1d) compared to control, supporting that depletion of HNF4A, and consequently reduced H3K4me1 and H3K27ac, diminish gene expression.”
Quote in the paperSubstantial claim - Findingown data
3207 regions (CL2) gained H3K4me1 in cells expressing HNF4A, regardless of HNF4A presence in 3T3 cells.
“We also looked at all H3K4me1 regions, regardless of HNF4A presence in 3T3 cells, and found 3207 regions (CL2) that gained the mark in cells expressing HNF4A (Supplementary Fig. 4 f, g).”
Quote in the paperSubstantial claim - Findingown data
After 3 days of HNF4A ectopic expression, the overall level of H3K4me1 was increased ~23% as observed by both western blotting and immunofluorescence.
“After 3 days of HNF4A ectopic expression, the overall level of H3K4me1 was increased (~23%) as observed by both western blotting (Fig. 4b and Supplementary Fig. 6b) and immunofluorescence (Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
HBRs clustered based on H3K4me1 enrichment into three clusters C1, C2 and C3.
“We clustered the HBRs based on H3K4me1 enrichment and identified three clusters (C1, C2 and C3) with C1 regions showing low enrichment of active histone modifications and low chromatin accessibility prior to HNF4A expression (Fig. 4d, e).”
Quote in the paperNot a substantial claim - Findingown data
C2 (1236 regions) maintained the same levels of histone modifications and accessibility following HNF4A expression.
“C2 (1236 regions) maintained the same levels of histone modifications and accessibility following HNF4A expression.”
Quote in the paperNot a substantial claim - Findingnone given
In the adult liver system, HNF4A was removed from an already differentiated state.
“In the adult liver HNF4A was removed from an already differentiated state while in the 3T3 cells expression of HNF4A caused a cell fate transition in a fibroblast cell line.”
Quote in the paperSubstantial claim - Findingown data
Within the regions newly activated with the addition of HNF4A, motifs for other TFs such as RXRG, RARA and ESRRA were found.
“However, other pioneer factors may facilitate chromatin opening since within the regions newly activated with the addition of HNF4A, we found motifs for other TFs such as RXRG, RARA and ESRRA indicating that additional mechanisms are likely involved.”
Quote in the paperNot a substantial claim - Findingown data
All HBR clusters showed increased MLL4 binding following HNF4A expression.
“Using the clusters identified in Fig. 4, all regions showed increased MLL4 binding following HNF4A expression (Fig. 5a, b).”
Quote in the paperSubstantial claim - Findingown data
UTX shRNA treatment had a similar effect to MLL4 shRNA on H3K4me1 and gene expression.
“We observed a similar effect in UTX shRNA treated cells.”
Quote in the paperSubstantial claim - Findingnone given
The vast majority of HBRs have associated H3K4me1 and H3K27ac.
“Since the vast majority of HBRs have associated H3K4me1 and H3K27ac, HNF4A likely does not have this scanning function in closed chromatin.”
Quote in the paperSubstantial claim - Findingreasoning
HNF4A is not bound to closed chromatin.
“While we have shown that HNF4A expression changes accessibility at a subset of regions and that it is capable of recruiting the MLL4 complex and encouraging histone modifications that activate an enhancer, HNF4A is not bound to closed chromatin.”
Quote in the paperSubstantial claim - Findingown data
HNF4A-bound regions correlated with MLL4 binding in cells where HNF4A was ectopically expressed.
“Similarly, we found that HNF4A-bound regions correlated with MLL4 binding in cells where HNF4A was ectopically expressed.”
Quote in the paperSubstantial claim - Findingown data
The C1 cluster shows a dramatic increase in MLL4 binding.
“The C1 cluster shows a dramatic increase in MLL4 binding.”
Quote in the paperNot a substantial claim - Findingown data
HNF4A associates with the MLL4 complex components ASH2L, UTX and RBBP5.
“Our studies demonstrate that HNF4A associates with the MLL4 complex components, ASH2L, UTX and RBBP5.”
Quote in the paperSubstantial claim - Findingown data
Within one week after the loss of HNF4A, H3K4me1 and H3K27ac levels are substantially reduced at HBRs.
“Within one week after the loss of HNF4A, H3K4me1 and H3K27ac levels are substantially reduced at HBRs.”
Quote in the paperSubstantial claim - Findingown data
HNF4A expression changes chromatin accessibility at a subset of regions.
“While we have shown that HNF4A expression changes accessibility at a subset of regions and that it is capable of recruiting the MLL4 complex and encouraging histone modifications that activate an enhancer, HNF4A is not bound to closed chromatin.”
Quote in the paperNot a substantial claim - Findingown data
HNF4A ectopic expression induced chromatin accessibility in cells lacking FOXA expression.
“Supporting this, we also observed that HNF4A ectopic expression induced chromatin accessibility in cells lacking FOXA expression.”
Quote in the paperNot a substantial claim - Findingown data
Using two different methods, HNF4A and the MLL4 complex physically interact in mouse liver and two cell lines expressing HNF4A.
“In addition, using two different methods we confirmed that HNF4A and the MLL4 complex physically interact in mouse liver and two cell lines expressing HNF4A.”
Quote in the paperSubstantial claim - Findingown data
An interaction between HNF4A and the MLL4 complex proteins ASH2L, RBBP5 and UTX was confirmed by co-immunoprecipitation in 3T3 cells ectopically expressing HNF4A.
“An interaction between HNF4A and the MLL4 complex proteins, ASH2L, RBBP5 and UTX, was confirmed by co-immunoprecipitation in 3T3 cells ectopically expressing HNF4A (Fig. 5d and Supplementary Fig. 6c).”
Quote in the paperSubstantial claim - Findingcitation
Public HepG2 ChIP-seq data suggested that HNF4A binds at the same regions as MLL4 complex proteins ASH2L and UTX and histone acetyltransferase p300.
“The HepG2 data for HNF4A, histone modifications, and MLL4 complex proteins suggested that HNF4A binds at the same regions as the complex proteins (ASH2L and UTX) and histone acetyltransferase (p300), which respectively establish H3K4me1 and H3K27ac on nearby nucleosomes (Supplementary Fig. 5a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites ENCODE
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
HNF4A can establish H3K4me1, H3K27ac and chromatin accessibility in unmarked chromatin when ectopically expressed in cell lines.
“Importantly, our data indicate that HNF4A is required for the maintenance of H3K4me1, H3K27ac and the open chromatin state at HBRs in vivo, and can establish these epigenetic features in unmarked chromatin when ectopically expressed in cell lines.”
Quote in the paperSubstantial claim - Study design and conductown data
With tamoxifen treatment, HNF4A is effectively depleted in hepatocytes within 1 week as confirmed by western blot.
“With tamoxifen treatment, HNF4A is effectively depleted in hepatocytes within 1 week as confirmed by western blot (Supplementary Figs. 1b and 7a) and we could examine the effects of acute HNF4A loss on histone modifications and chromatin in the adult liver.”
Quote in the paperSubstantial claim - Interpretationown data
HNF4A, rather than FOXA proteins, is essential to maintain histone signatures.
“suggesting that HNF4A, rather than FOXA proteins, is essential to maintain histone signatures.”
Quote in the paperSubstantial claim - Interpretationown data
Binding by HNF4A may be transient at some locations.
“This suggests that binding by HNF4A may be transient at some locations.”
Quote in the paperNot a substantial claim - Interpretationown data
HNF4A is required to maintain H3K4me1 at HBRs.
“suggesting that HNF4A is required to maintain H3K4me1 at HBRs.”
Quote in the paperSubstantial claim - Study design and conductown data
FOXA1, FOXA2 and FOXA3 were not induced in the HNF4A ectopic expression 3T3 system.
“Of note, FOXA1, FOXA2 and FOXA3 were not induced in this system, making this model suitable to examine the exclusive role HNF4A has on shaping the epigenetic landscape.”
Quote in the paperSubstantial claim - Interpretationown data
HNF4A ectopic expression causes 3T3 cells to undergo a mesenchyme to epithelial shift.
“This alongside the physical observations, indicate that these cells are undergoing a mesenchyme to epithelial shift.”
Quote in the paperNot a substantial claim - Interpretationcitation
At the majority of binding sites, HNF4A remains bound regardless of the presence of any FOXAs.
“Thus, at the majority of binding sites, HNF4A remains bound, regardless of the presence of any FOXAs, suggesting that HNF4A, rather than FOXA proteins, is essential to maintain histone signatures.”
Quote in the paperSubstantial claim - Interpretationreasoning
HNF4A likely does not have the scanning function of pioneer factors in closed chromatin.
“Since the vast majority of HBRs have associated H3K4me1 and H3K27ac, HNF4A likely does not have this scanning function in closed chromatin.”
Quote in the paperSubstantial claim - Interpretationown data
HNF4A is required for the recruitment of the MLL4 complex to enhancers to establish and maintain a transcriptionally permissive state.
“Our data indicate that HNF4A is required for the recruitment of this complex to enhancers to establish and maintain a transcriptionally permissive state.”
Quote in the paperSubstantial claim - Interpretationreasoning
HNF4A can promote the open chromatin state.
“This indicates that HNF4A can promote the open chromatin state.”
Quote in the paperNot a substantial claim - Interpretationown data
HNF4A can maintain H3K4me1 and H3K27ac in livers in the absence of FOXA.
“This indicates that HNF4A can maintain H3K4me1 and H3K27ac in livers in the absence of FOXA.”
Quote in the paperSubstantial claim - Interpretationown data
Additional mechanisms beyond HNF4A are likely involved in the activation of the regions newly activated with the addition of HNF4A.
“However, other pioneer factors may facilitate chromatin opening since within the regions newly activated with the addition of HNF4A, we found motifs for other TFs such as RXRG, RARA and ESRRA indicating that additional mechanisms are likely involved.”
Quote in the paperNot a substantial claim - Interpretationown data
HNF4A binding to HBRs promotes recruitment of MLL4.
“This suggests that HNF4A binding to these regions promotes recruitment of MLL4.”
Quote in the paperSubstantial claim - Interpretationnone given
In 3T3 cells, ectopic expression of HNF4A caused a cell fate transition in a fibroblast cell line.
“In the adult liver HNF4A was removed from an already differentiated state while in the 3T3 cells expression of HNF4A caused a cell fate transition in a fibroblast cell line.”
Quote in the paperNot a substantial claim - Interpretationreasoning
HNF4A joins a growing class of TFs that act by recruiting the required machinery to initiate and maintain enhancer histone modifications.
“Thus, HNF4A joins a growing class of TFs that act by recruiting the required machinery to initiate and maintain enhancer histone modifications.”
Quote in the paperSubstantial claim - Interpretationreasoning
HNF4A appears to function to coordinate the active chromatin state.
“Given that HNF4A interacts with the MLL4 complex, TET proteins and histone acetyltransferases, HNF4A appears to function to coordinate the active chromatin state.”
Quote in the paperSubstantial claim - Interpretationreasoning
HNF4A facilitates the formation of a transcriptionally permissive hub by recruiting the epigenetic machinery to drive cell-type-specific gene expression.
“Overall, these findings suggest that HNF4A facilitates the formation of a transcriptionally permissive hub by recruiting the epigenetic machinery to drive cell-type-specific gene expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
Additional factors are required to facilitate opening of chromatin at HNF4A-bound regions.
“the lack of other defining features of a pioneer factor suggest that additional factors are required to facilitate opening of chromatin”
Quote in the paperSubstantial claim - Interpretationreasoning
HNF4A interacts with the epigenetic modifier MLL4 to deposit H3K4me1 at HBRs.
“Here, we propose a mechanism whereby HNF4A, a regulator of hepatocyte identity, interacts with the epigenetic modifier MLL4 to deposit H3K4me1 at HBRs.”
Quote in the paperSubstantial claim - Interpretationreasoning
Changes in overall genomic patterns may not be generalized to all genes.
“Thus, changes in overall genomic patterns may not be generalized to all genes.”
Quote in the paperNot a substantial claim- Rests on an assumption: Precise mapping of enhancers to genes is often inaccurate.
- Rests on an assumption: Most genes are regulated by multiple enhancers because redundancy is built into gene regulatory mechanisms.
- Interpretationreasoning
The aberrant epigenetic program upon loss or reduced expression of HNF4A can contribute to disease progression, such as in hepatocellular carcinoma.
“These findings provide a greater understanding of how the aberrant epigenetic program, upon loss or reduced expression of HNF4A, can contribute to disease progression, such as in hepatocellular carcinoma.”
Quote in the paperSubstantial claim - Interpretationown data
Distinct gene regulatory elements can produce similar changes in gene expression due to tissue-specific facets.
“These examples highlight how distinct gene regulatory elements can produce similar changes in gene expression due to tissue-specific”
Quote in the paperNot a substantial claim - Interpretationown data
HNF4A plays an essential role in liver by establishing and maintaining the epigenetic landscape via direct interaction with the MLL4 complex.
“In summary, our work demonstrates the essential role that HNF4A plays in liver by establishing and maintaining the epigenetic landscape via direct interaction with the MLL4 complex.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 30
- May combine two claims. 47
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMLL4 exists in a multi-protein complex containing core components WDR5, ASH2L, RBBP5 and DPY30 and other complex-specific proteins such as PAGR1, KDM6A, NCOA6 and PAXIP1.
“MLL4 exists in a multi-protein complex containing the core components WDR5, ASH2L, RBBP5 and DPY3038,39 and other complex-specific proteins, such as PAGR1 (previously known as PA1), KDM6A (UTX), NCOA6 and PAXIP1 (PTIP)37,40.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [38] Wang, L.-H., Aberin, M. A. E., Wu, S. & Wang, S.-P. The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape. Biochem. Soc. Trans. 49, 1041–1054 (2021). source
- cites [39] Ernst, P. & Vakoc, C. R. WRAD: enabler of the SET1-family of H3K4 methyltransferases. Brief. Funct. Genomics 11, 217–26 (2012). source
- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
The Results (Figure 4F; page unavailable) identify UTX, PTIP and PA1 as MLL3/MLL4 complex components, supporting the cited portion of the sentence for KDM6A, PAXIP1 and PAGR1. Our copy does not identify NCOA6 as a component. The citation to this paper is attached to the complex-specific proteins, not the preceding list of core components. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [40] Piunti, A. & Shilatifard, A. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science 352, aad9780 (2016). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationH3K4me1 in combination with H3K27ac designates the active enhancer state, while H3K4me1 alone, or with H3K27me3, defines a primed or repressed enhancer, respectively.
“Monomethylation on H3K4 (H3K4me1) in combination with acetylation of H3 at K27 (H3K27ac) designates the active enhancer state33 while H3K4me1 alone, or with trimethylation of H3K27 (H3K27me3), defines a primed or repressed enhancer, respectively30.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [33] Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–6 (2010). source
- cites [30] Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–37 (2013). source
Classified as probably not a substantial claim.
PremisecitationActive and primed enhancers are marked by H3K4me1 in a cell type-specific manner.
“In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner.”
- Also stated in: § Introduction · plain
“Enhancers are marked with a unique set of epigenetic signatures29–31 with methylation of histone 3 at lysine 4 (H3K4me) as a key histone modification32.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [29] Bulger, M. & Groudine, M. Functional and mechanistic diversity of distal transcription enhancers. Cell 144, 327–39 (2011). source
- cites [30] Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–37 (2013). source
- cites [31] Ong, C. T. & Corces, V. G. Enhancers: emerging roles in cell fate specification. EMBO Rep. 13, 423–30 (2012). source
- cites [32] Robertson, A. G. et al. Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding. Genome Res. 18, 1906–17 (2008). source
The Abstract (page unavailable) identifies H3K4me1 as a dominant mark of active and potentially active distal regulatory regions, supporting the active-and-primed portion of the claim. It compares HeLa cells with mouse liver and says modification combinations may vary between biological systems, but it does not establish that enhancer marking is cell type-specific. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Also stated in: § Introduction · plain
May combine two claims.
Premisenone givenHNF4A controls genes that are crucial for liver functions, primarily through binding to enhancers.
“Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers.”
- Also stated in: § Introduction · plain
“In the case of HNF4A, the majority of DNA-binding sites are found at enhancers.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [1] Sladek, F. M., Zhong, W. M., Lai, E. & Darnell, J. E. Jr. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 4, 2353–65 (1990). source
The Abstract and “HNF-4 and liver-specific gene expression” section describe HNF-4 binding to sites in, and helping regulate, genes with liver-related functions. But “Purification and characterization of HNF-4 protein” identifies key sites in the TTR and apoCIII promoters; the paper does not establish that HNF-4 acts primarily through enhancers. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [2] Dubois, V., Staels, B., Lefebvre, P., Verzi, M. P. & Eeckhoute, J. Control of cell identity by the nuclear receptor HNF4 in organ pathophysiology. Cells 9, 2185 (2020). source
Section 3.2 says HNF4 controls genes involved in liver-specific functions through binding to regulatory regions. It also says HNF4A binds substantially to promoters—including those of almost half the actively transcribed genes in adult liver—so the claim that it acts primarily through enhancers is not supported by this passage. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [3] Lau, H. H., Ng, N. H. J., Loo, L. S. W., Jasmen, J. B. & Teo, A. K. K. The molecular functions of hepatocyte nuclear factors—in and beyond the liver. J. Hepatol. 68, 1033–1048 (2018). source
- Also stated in: § Introduction · plain
Classified as probably not a substantial claim.
PremisecitationMLL4, alongside MLL3, is a histone methyltransferase that establishes H3K4me1/2 at enhancers in mammalian cells.
“Mixed-lineage leukaemia 4 (MLL4, also known as KMT2D), alongside the closely related MLL3 (KMT2C), is a histone methyltransferase that establishes H3K4me1/2 at enhancers in mammalian cells35–37.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [35] Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604–20 (2012). source
The section “The mammalian homolog of Trr, Mll3, is also a major monomethyltransferase” reports reduced enhancer-associated H3K4me1 in Mll3-knockout mouse cells; Figure 7C proposes H3K4me1 activity for mammalian Mll3/Mll4 complexes. These passages support the H3K4me1 portion, but not the claim that MLL3 and MLL4 establish H3K4me2 at enhancers. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [36] Hu, D. et al. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell Biol. 33, 4745–54 (2013). source
- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLoss of H3K4me1 reduces H3 eviction from the region.
“which may be a result of the fact that the loss of H3K4me1 reduces H3 eviction from the region34.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [34] Kang, Y., Kim, Y. W., Kang, J. & Kim, A. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers. Faseb j. 35, e21781 (2021). source
May combine two claims.
InterpretationcitationFOXA2 can be bound to closed or unmarked regions, suggesting additional factors may be required to activate these regions when needed.
“As FOXA2 is a known pioneer factor51, it can be bound to closed or unmarked regions, suggesting additional factors may be required to activate these regions when needed.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [51] Iwafuchi-Doi, M. et al. The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Mol. Cell 62, 79–91 (2016). source
The Results section on FoxA2 binding identifies it as a pioneer factor, and the Discussion describes pioneer factors helping other transcription factors access their sites. But the Results report that most FoxA2 sites overlap DNase-hypersensitive regions and that FoxA did not bind the silent enhancers examined. Our copy does not establish FOXA2 binding at closed or unmarked regions, or that additional factors are required to activate those regions. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationWhile MLL4 is required for cell fate transition, not all enhancers are primed prior to differentiation and MLL4 is not required for the maintenance of cell identity.
“Interestingly, while MLL4 is required for cell fate transition, not all enhancers are primed prior to differentiation and MLL4 is not required for the maintenance of cell identity41.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [41] Wang, C. et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proc. Natl Acad. Sci. USA 113, 11871–11876 (2016). source
Classified as probably not a substantial claim.
PremisecitationSome studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers.
“While some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers44–47, whether HNF4A has this function is not known.”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [44] Lee, J. E., Cho, Y. W., Deng, C. X. & Ge, K. MLL3/MLL4-associated PAGR1 regulates adipogenesis by controlling induction of C/EBPβ and C/EBPδ. Mol. Cell Biol. 40, e00209–20 (2020). source
The Discussion describes MLL3/MLL4-associated PAGR1 regulating adipogenic transcription factors, and the Regulation of gene expression by PAGR1 section describes signal-activated CREB recruiting PAGR1 to a promoter. Neither passage says that transcription factors recruit MLL4 to enhancers to establish H3K4me1. Searches for H3K4me1, MLL4 recruitment, and enhancer methylation found no passage establishing that mechanism in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [45] Patel, S. R., Kim, D., Levitan, I. & Dressler, G. R. The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev. Cell 13, 580–92 (2007). source
- cites [46] Scoville, D. W. et al. MLL3 and MLL4 methyltransferases Bind to the MAFA and MAFB transcription factors to regulate islet β-cell function. Diabetes 64, 3772–83 (2015). source
The Discussion (page unavailable) reports that the islet β-cell transcription factors MAFA and MAFB recruit MLL3/4 complexes, supporting the recruitment part of the claim. It reports H3K4 trimethylation at a regulated gene, however, not establishment of H3K4me1 at enhancers; the Results describe enhancer monomethylation as a general capability of the methyltransferase family rather than a finding of this study. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [47] Sun, Y. et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell 34, 643–658.e5 (2018). source
Classified as probably not a substantial claim.
PremisecitationMLL4 binding at enhancers coincides with the binding of master regulators.
“MLL4 binding at enhancers has been shown to coincide with the binding of master regulators42–44.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [42] Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–89 (2010). source
The section ‘PU.1 induces sequential nucleosome remodelling and histone H3K4 monomethylation’ reports that distal sites bound by lineage-determining factors are associated with H3K4me1, a mark of enhancer-like regions. That supports the enhancer–regulator association, but the paper does not establish that MLL4 itself binds at those sites or coincides with the regulators. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [43] Egolf, S. et al. MLL4 mediates differentiation and tumor suppression through ferroptosis. Sci. Adv. 7, eabj9141 (2021). source
The Results section reports that MLL4 binds enhancers and that motifs for the master epithelial regulator p63 and for p53 are enriched at MLL4 binding sites. It also reports interactions between MLL4 and those factors, but motif enrichment and protein interaction do not establish that the factors bind the same enhancers at the same time. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [44] Lee, J. E., Cho, Y. W., Deng, C. X. & Ge, K. MLL3/MLL4-associated PAGR1 regulates adipogenesis by controlling induction of C/EBPβ and C/EBPδ. Mol. Cell Biol. 40, e00209–20 (2020). source
The Discussion says MLL3/MLL4 control induction of master adipogenic transcription factors, and the References list an earlier study on MLL4 and enhancer activation. Neither passage says that MLL4 binding at enhancers coincides with master-regulator binding; searches for MLL4 binding and enhancer co-occupancy found no such statement in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLoss of function mutations in MLL4 reduce global H3K4me1 levels, cause abnormal gene expression, and lead to developmental defects or cancer.
“Loss of function mutations in MLL4 reduce global H3K4me1 levels, cause abnormal gene expression, and lead to developmental defects or cancer37.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
The Results report global H3K4me1 decreases after Mll4 deletion in Mll3-knockout cells and reduced expression of enhancer-associated genes after Mll4 deletion. The Discussion links MLL4 loss-of-function mutations to developmental diseases and cancers, but says the proposed mechanism “may contribute” to their pathogenesis; it does not establish that those mutations cause cancer. The global H3K4me1 result also comes from cells lacking both MLL3 and MLL4, not MLL4 alone. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMLL4 is known to exist at enhancers in a complex with UTX (KDM6A), ASH2L, and RBBP5.
“MLL4 is known to exist at enhancers in a complex with UTX (KDM6A), ASH2L, and RBBP538.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Wang, L.-H., Aberin, M. A. E., Wu, S. & Wang, S.-P. The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape. Biochem. Soc. Trans. 49, 1041–1054 (2021). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMLL4 is required for H3K27ac, Pol II, and mediator recruitment to enhancers.
“It has been shown that MLL4 is required for H3K27ac, Pol II, and mediator recruitment to enhancers37”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHNF4A has been shown to interact with the histone acetyltransferase p300, although whether this is direct or through the MLL4 complex has not been confirmed.
“Moreover, HNF4A has been shown to interact with the histone acetyltransferase, p30062,63, although whether this is direct or through the MLL4 complex has not been confirmed.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [62] Eeckhoute, J., Formstecher, P. & Laine, B. Hepatocyte nuclear factor 4alpha enhances the hepatocyte nuclear factor 1alpha-mediated activation of transcription. Nucleic Acids Res. 32, 2586–93 (2004). source
- cites [63] Ruse, M. D. Jr., Privalsky, M. L. & Sladek, F. M. Competitive cofactor recruitment by orphan receptor hepatocyte nuclear factor 4alpha1: modulation by the F domain. Mol. Cell Biol. 22, 1626–38 (2002). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRecent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin.
“recent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin41,61.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [41] Wang, C. et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proc. Natl Acad. Sci. USA 113, 11871–11876 (2016). source
The Significance section reports that MLL4 is required for p300 recruitment and H3K27ac deposition at de novo enhancers during embryonic stem-cell differentiation; the paper also identifies MLL4 as an H3K4 methyltransferase. Our copy does not show that UTX participates in this mechanism or that MLL4 activates p300's enzymatic activity, rather than enabling its recruitment. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [61] Lai, B. et al. MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis. Nucleic Acids Res. 45, 6388–6403 (2017). source
The Discussion (page unavailable) says MLL3/MLL4 facilitate CBP/p300 binding at enhancers and links the proteins to H3K4 methylation and H3K27 acetylation. The Results (Figure 5F; page unavailable) show that MLL4 interacts with UTX, but the paper does not establish that UTX mediates CBP/p300 recruitment or that the MLL4 complex activates p300 enzymatic activity. The Discussion says the binding mechanism remains unknown. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEctopic expression of C/EBPβ in preadipocytes recruited MLL4 to establish adipogenic enhancers.
“Ectopic expression of C/EBPβ in preadipocytes recruited MLL4 to establish adipogenic enhancers.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHNF4A cooperates with the FOXA family and GATA6 of pioneer factors.
“HNF4A is known to cooperate with the FOXA family and GATA6 of pioneer factors12,49,55.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [12] Sekiya, S. & Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475, 390–3 (2011). source
- cites [49] Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–71 (2014). source
The Results section, “Widespread Combinatorial Role for HNF4A and FOXA2 in the Embryonic Liver,” describes cooperation and shared binding between HNF4A and FOXA2. The cited paper does not establish cooperation with the FOXA family as a whole or with GATA6; a search for GATA6 found no relevant passage in our copy. Page numbers were not available. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [55] Wallerman, O. et al. Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing. Nucleic Acids Res 37, 7498–508 (2009). source
The Results section ('Co-identified motifs in peaks correspond to in vivo binding'; page not available) says FOXA2 is known to bind with HNF4a and reports FOXA motifs near HNF4a sites. The Introduction identifies FOXA2 as a pioneering factor. These passages support cooperation with FOXA2, but the copy does not establish cooperation with the FOXA family generally or with GATA6 (searched: GATA6). (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationMLL4 serves as a main H3K4 mono-methyltransferase for enhancer activation and exhibits cell type and differentiation stage specific binding.
“MLL4 serves as a main H3K4 mono-methyltransferase for enhancer activation35,36,38 and exhibits cell type and differentiation stage specific binding37,41.”
Quote in the paperSubstantial claim4 of 5 sources checked- cites [35] Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604–20 (2012). source
The section 'The mammalian homolog of Trr, Mll3, is also a major monomethyltransferase' reports reduced enhancer-associated H3K4me1 in Mll3-knockout fibroblasts and proposes a role for Mll3/Mll4 complexes in enhancer activation. It does not directly establish that MLL4 itself is a main monomethyltransferase; Mll4's contribution is presented as possible functional redundancy. The cell-type and differentiation-stage binding clause carries different citations, so it is not attributed to this source here. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [36] Hu, D. et al. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell Biol. 33, 4745–54 (2013). source
- cites [38] Wang, L.-H., Aberin, M. A. E., Wu, S. & Wang, S.-P. The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape. Biochem. Soc. Trans. 49, 1041–1054 (2021). source
The section on catalytic and noncatalytic function in enhancer activation identifies MLL3/4 as major H3K4me1 methyltransferases and describes their role at enhancers, supporting the first part of the claim, though it discusses MLL3 and MLL4 together. The section on MLL3/4 complexes describes recruitment to particular enhancers, but the retrieved passages do not establish that MLL4 binding varies specifically by cell type and differentiation stage. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
- cites [41] Wang, C. et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proc. Natl Acad. Sci. USA 113, 11871–11876 (2016). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationMLL3 and MLL4 catalyze H3K4 monomethylation and are recruited to target enhancers by TFs and pioneer factors.
“MLL3 and MLL4 catalyze H3K4 monomethylation and are recruited to target enhancers by TFs and pioneer factors37,38,59.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
The Introduction identifies MLL4 as a major H3K4 mono- and di-methyltransferase that is partially redundant with MLL3. The Results and Discussion say that lineage-determining TFs, including the pioneer TF C/EBPβ, recruit MLL4 to enhancers. Our copy does not establish that MLL3 is likewise recruited by those factors. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [38] Wang, L.-H., Aberin, M. A. E., Wu, S. & Wang, S.-P. The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape. Biochem. Soc. Trans. 49, 1041–1054 (2021). source
- cites [59] Sze, C. C. & Shilatifard, A. MLL3/MLL4/COMPASS family on epigenetic regulation of enhancer function and cancer. Cold Spring Harb. Perspect. Med. 6, a026427 (2016). source
The Drosophila section identifies MLL3/MLL4 as key H3K4 monomethyltransferases at enhancers. The section on models for malfunction discusses possible interactions with transcription factors, but says that identifying the key players that bring MLL3/MLL4 to enhancers remains an open question; it does not establish recruitment by TFs and pioneer factors. Page numbers were not available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationH3K27ac at gene regulatory regions is dependent on the presence of H3K4me1, indicating H3K4me1 defines the future active enhancer.
“The active histone modification H3K27ac at gene regulatory regions is dependent on the presence of H3K4me1, indicating H3K4me1 defines the future active enhancer30,34.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [30] Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–37 (2013). source
In “H3K4me1 at enhancers: a window of opportunity for enhancer deployment” (page not provided), the review says H3K27ac is acquired almost exclusively where H3K4me1 already exists. But it describes H3K4me1 as perhaps defining—or merely correlating with—a broad window for activation, not as determining which enhancers will become active. The claim overstates both dependence and predictive specificity. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [34] Kang, Y., Kim, Y. W., Kang, J. & Kim, A. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers. Faseb j. 35, e21781 (2021). source
The genome-wide analysis section states that H3K27ac depends on H3K4me1 at putative enhancers. The eRNA transcription section also describes enhancers as prepared by H3K4me1. Neither passage establishes that H3K4me1 identifies which enhancers will become active in the future. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMLL4 co-localizes with lineage-specific TFs such as C/EBPβ, PPARγ, EBF1 and GR at enhancers to ensure increased expression of cell-type-specific genes that establish lineage maturity.
“MLL4 has also been shown to co-localize with lineage-specific TFs such as C/EBPβ, PPARγ, EBF1 and GR at enhancers to ensure increased expression of cell-type-specific genes that establish lineage maturity37.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Lee, J.-E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). source
The Results sections on genomic co-localization and active enhancers show MLL4 co-localizing with C/EBPβ and PPARγ at adipogenic enhancers. The Results section on cell-type-specific gene expression reports that Mll4 deletion reduces expression of genes associated with MLL4-positive enhancers. For EBF1 and GR, however, the paper reports enriched binding motifs at MLL4 sites, not measured co-localization; it also does not establish that the affected genes confer lineage maturity. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataApoc2 gene was significantly downregulated in the cKO liver and upregulated in cells expressing HNF4A.
“An example is shown in the Apoc2 gene, which was significantly downregulated in the cKO liver and upregulated in the cells expressing HNF4A (Fig. 4g and Supplementary Data 1, 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataC3 (1905 regions) showed a substantial increase of H3K4me1 and H3K27ac around HBRs, although low levels of histone modification were present in control samples suggesting that these regions were already accessible.
“Similar to C1, C3 (1905 regions) showed a substantial increase of H3K4me1 and H3K27ac around HBRs, although low levels of histone modification were present in control samples suggesting that these regions were already accessible.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSet2, with both FOXA2 and HNF4A bound, showed a reduction of H3K4me1 but maintained nucleosome positioning with no drastic change in H3K27ac and accessibility in the Hnf4a cKO.
“Set2, with both FOXA2 and HNF4A bound, showed a reduction of H3K4me1 but maintained nucleosome positioning with no drastic change in H3K27ac and accessibility in the Hnf4a cKO.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CL2, motif analysis found JUND and HNF4A as the most significant, with the HNF4A motif represented in over 96% of newly methylated regions.
“motif analysis found JUND and HNF4A as the most significant in this cluster with the HNF4A motif represented in over 96% of these newly methylated regions (Supplementary Fig. 4h).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataHNF4A binding motifs were similar between HBRs in the expression system and adult liver.
“although HNF4A binding motifs were similar (Supplementary Fig. 4c).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCUT&Tag identified 4083 HNF4A-bound regions in HNF4A-expressing 3T3 cells, preferentially at intronic and distal intergenic regions, similar to adult liver.
“We used CUT&Tag to identify where HNF4A bound in the induced system and identified 4083 HNF4A-bound regions in these cells preferentially at intronic and distal intergenic regions, similar to the adult liver (Fig. 4a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRNA-seq analysis of genes associated within the common 839 regions show significantly increased expression in HNF4A-expressing 3T3 cells and significantly decreased expression in Hnf4a cKO livers compared to controls.
“RNA-seq analysis of genes associated within this subset of bound regions show significantly increased expression in HNF4A-expressing 3T3 cells and significantly decreased expression in Hnf4a cKO livers compared to their respective controls (Supplementary Fig. 4e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataC1 regions (942) had low enrichment of active histone modifications and low chromatin accessibility prior to HNF4A expression and became newly activated with high H3K4me1, H3K27ac and ATAC-seq signal only after HNF4A expression.
“These 942 regions became newly activated with high H3K4me1, H3K27ac and ATAC-seq signal only after HNF4A expression and motif analysis showed HNF4A as the most significantly enriched (Fig. 4f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEpithelial related genes (Id2, Id3, Erf, Tjp1, Cebpb) were upregulated and mesenchyme related genes (Twist1, Snai1, Zeb1, Vim) were downregulated in HNF4A EE cells.
“Epithelial related genes, such as Id2, Id3, Erf, Tjp1, and Cebpb, were upregulated while mesenchyme related genes, such as Twist1, Snai1, Zeb1 and Vim, were downregulated (Fig. 3e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt the sites where HNF4A binding is lost with FOXA loss, H3K4me1 and H3K27ac were reduced in TFKOs, while the majority of normally co-bound sites maintained strong HNF4A binding and intact histone modifications regardless of FOXA loss.
“At these sites alone, there was a reduction in H3K4me1 and H3K27ac in TFKOs while the majority of normally co-bound sites maintained strong HNF4A binding and the histone modifications remained intact regardless of loss of FOXAs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSimilar effects of HNF4A on overall genomic changes were observed in the two systems studied.
“In our studies, we observed similar effects of HNF4A on overall genomic changes.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHNF4A is capable of recruiting the MLL4 complex and encouraging histone modifications that activate an enhancer.
“While we have shown that HNF4A expression changes accessibility at a subset of regions and that it is capable of recruiting the MLL4 complex and encouraging histone modifications that activate an enhancer, HNF4A is not bound to closed chromatin.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe C2 cluster showed very strong H3K4me1 signal regardless of HNF4A presence, and MLL4 signal increased further with HNF4A binding.
“Interestingly, while the C2 cluster showed very strong H3K4me1 signal, regardless of HNF4A presence, the MLL4 signal increased further with HNF4A binding.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe C3 cluster had low H3K4me1 and MLL4 bound in control 3T3 cells, and both increased with HNF4A binding.
“The C3 cluster, with low H3K4me1 and MLL4 bound in control 3T3 cells, had both increased with HNF4A binding (Figs. 4d, 5b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataProximity ligation assay validated the association between HNF4A and MLL4 or HNF4A and ASH2L proteins in situ in 3T3 cells and HEK293T cells ectopically expressing HNF4A.
“Proximity ligation assay (PLA) validated the association between HNF4A and MLL4 or HNF4A and ASH2L proteins in situ in 3T3 cells (Fig. 5e and Supplementary Fig. 5c) and HEK293T cells (Supplementary Fig. 5d, e) ectopically expressing HNF4A.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoc2 is downregulated in the Hnf4a cKO mouse liver, where HNF4A is bound at the Apoc2 promoter region.
“For example, Apoc2 is downregulated in the Hnf4a cKO mouse liver where HNF4A is bound at the Apoc2 promoter region.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEctopic expression of HNF4A in control shRNA-transduced 3T3 cells increased H3K4me1 at HBRs and increased gene expression of Apoc2 and Aqp1.
“Ectopic expression of HNF4A in control shRNA-transduced cells increased H3K4me1 at the HBRs. Moreover, their gene expression levels were increased.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningIn the Hnf4a cKO mouse liver, there are no changes in chromatin accessibility or histone modifications at Apoc2.
“However, there are no changes in the chromatin accessibility or histone modifications, likely reflecting that other factors are present at promoters.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHNF4A-MLL4 complex interactions also occur in HEK293T cells overexpressing HNF4A and in mouse livers where HNF4A is endogenously expressed.
“These interactions were confirmed to also occur in HEK293T cells (overexpressing HNF4A) as well as in mouse livers where HNF4A is endogenously expressed (Supplementary Figs. 5b, 6c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIdo2 expression was drastically reduced in the Hnf4a cKO livers while it was not altered (remained off) in the cell system.
“In contrast, Ido2 expression was drastically reduced in the Hnf4a cKO livers while it was not altered (remained off) in the cell system.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataApoc2 is upregulated in 3T3 cells ectopically expressing HNF4A, where HNF4A is bound at an intronic enhancer and levels of histone modifications are increased.
“In contrast, Apoc2 is upregulated in 3T3 cells ectopically expressing HNF4A, where HNF4A is bound at an intronic enhancer and levels of histone modifications are increased.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataDepletion of HNF4A, and consequently reduced H3K4me1 and H3K27ac, diminish gene expression.
“supporting that depletion of HNF4A, and consequently reduced H3K4me1 and H3K27ac, diminish gene expression.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHNF4A is required for the maintenance of H3K4me1, H3K27ac and the open chromatin state at HBRs in vivo.
“Importantly, our data indicate that HNF4A is required for the maintenance of H3K4me1, H3K27ac and the open chromatin state at HBRs in vivo, and can establish these epigenetic features in unmarked chromatin when ectopically expressed in cell lines.”
- Also stated in: § HNF4A depletion in adult mouse liver alters histone modifications and chromatin accessibility · plain
“In summary, the loss of HNF4A initiates a reduction of H3K4me1 and H3K27ac at HBRs, as well as a decrease in chromatin accessibility.”
Quote in the paperSubstantial claim- Also stated in: § HNF4A depletion in adult mouse liver alters histone modifications and chromatin accessibility · plain
May combine two claims.
Interpretationown dataMany HBRs are unique across cell types and HNF4A does not bind all genomic regions where a motif is evident.
“This highlights that many HBRs are unique across cell types and HNF4A does not bind all genomic regions where a motif is evident.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHNF4A interacts with the MLL4 histone methyltransferase complex and recruits it to HBRs.
“Finally, we demonstrate that HNF4A interacts with the MLL4 histone methyltransferase complex and recruits it to HBRs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBinding of HNF4A in cells that do not normally express HNF4A causes an increase in H3K4me1, H3K27ac and chromatin accessibility and can establish H3K4me1 to activate a unique set of regulatory regions that initiate a shift from a mesenchymal to epithelial cell state.
“Our data suggests that binding of HNF4A in cells that do not normally express HNF4A causes an increase in H3K4me1, H3K27ac and chromatin accessibility and can establish H3K4me1 to activate a unique set of regulatory regions that initiate a shift from a mesenchymal to epithelial cell state.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningA stepwise model in which HNF4A binds genomic regions containing the HNF4A motif, recruits TET proteins and MLL4, resulting in hydroxymethylation of cytosine and monomethylation of H3K4; p300 recruited by the MLL4 complex then marks nucleosomes by H3K27ac; these modifications cause changes in charge to histones, contributing to loosening of DNA bound to the nucleosome, increasing accessibility and
“Based on these findings, we propose a stepwise model (Fig. 6) where HNF4A binds genomic regions containing the HNF4A motif, recruits TET proteins and MLL4, resulting in hydroxymethylation of cytosine and monomethylation of H3K4. With p300 being recruited by the MLL4 complex, the nucleosomes are then marked by H3K27ac. These modifications cause changes in charge to the histones, which contributes”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPhysical interactions between HNF4A and proteins in the MLL4 complex, in vitro and in vivo, act to recruit MLL4 to enhancers to establish H3K4me1 causing a cascade effect that activates the enhancer to induce gene expression.
“Together, our findings suggest that the physical interactions between HNF4A and proteins in the MLL4 complex, in vitro and in vivo, act to recruit MLL4 to enhancers to establish H3K4me1 causing a cascade effect that activates the enhancer to induce gene expression.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIn the C2 and C3 clusters, the regions are already active but binding of HNF4A augments their activity.
“This suggests that in these two clusters the regions are already active but binding of HNF4A augments their activity.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHNF4A is essential for maintaining H3K4me1 at HBRs, and consequently H3K27ac, in the adult mouse liver.
“we show that HNF4A is essential for maintaining H3K4me1 at HBRs, and consequently H3K27ac, in the adult mouse liver.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEctopic expression of HNF4A can augment H3K4me1 and H3K27ac and, at a subset of sites, can dramatically increase chromatin accessibility alongside the active histone modifications.
“We further show, using an in vitro system, that ectopic expression of HNF4A can augment H3K4me1 and H3K27ac and, at a subset of sites, can dramatically increase chromatin accessibility alongside the active histone modifications.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe absence of chromatin accessibility and histone modification changes at Apoc2 in cKO liver likely reflects that other factors are present at promoters.
“However, there are no changes in the chromatin accessibility or histone modifications, likely reflecting that other factors are present at promoters.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningHNF4A establishes enhancers as active, with open chromatin marked by H3K4me1 and H3K27ac, and facilitates how these enhancers interact with the nearby promoter.
“Together these data indicate that HNF4A establishes enhancers as active, with open chromatin marked by H3K4me1 and H3K27ac, and facilitates how these enhancers interact with the nearby promoter.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataATAC-seq levels are reduced at HBRs after HNF4A loss, indicating that changes in chromatin structure are initiated.
“Moreover, ATAC-seq levels are reduced, indicating that changes in chromatin structure are initiated.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe fundamental difference between the two systems accounts for the distinct HNF4A-bound regions and how gene expression is managed in the two systems.
“These differences account for distinct HNF4A-bound regions and how gene expression is managed in the two systems.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHNF4A-mediated induction of H3K4me1 at HBRs and the subsequent gene transcription depend on the MLL4 complex.
“Overall, our data support that HNF4A-mediated induction of H3K4me1 at HBRs and the subsequent gene transcription depend on the MLL4 complex.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study complied with all relevant ethical regulations for animal use.
“We have complied with all relevant ethical regulations for animal use.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenWestern blots, Co-IP and PLA experiments were completed multiple times to ensure reproducibility, with a representative shown.
“Western blots, Co-IP and PLA experiments were completed multiple times to ensure reproducibility with a representative shown.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataHNF4A expression was confirmed by detecting GFP expression, RT-qPCR and western blot analysis.
“HNF4A expression was confirmed by detecting GFP expression, RT-qPCR and western blot analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataChIP-seq, CUT&Tag and ATAC-seq were each completed only once, although qPCR was used for validation (not shown).
“ChIP-seq, CUT&Tag and ATAC-seq were all completed only once although qPCR was used for validation (not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll mouse protocols were approved for ethics by the Animal Care Committee, University of British Columbia.
“All mouse protocols were approved for ethics by the Animal Care Committee, University of British Columbia.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone givenHNF4A regulates MET and the epithelial phenotype of cells.
“Our work also highlights the role of HNF4A in regulating MET and the epithelial phenotype of cells, and we provide a mechanism for HNF4A-controlled gene regulation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe HNF4a knockout animal studies and procedures were carried out in accordance with the National Cancer Institute Animal Care and Use Committee.
“The HNF4a knockout animal studies and procedures were carried out in accordance with the National Cancer Institute Animal Care and Use Committee.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRNA-seq was done on 3 biological replicates.
“RNA-seq was done on 3 biological replicates.”
- Also stated in: § RNA-seq and analysis · plain
“Three biological replicates were used for RNA extraction followed by sequencing at the University of British Columbia (now SBME Sequencing Facility).”
Quote in the paperNot a substantial claim- Also stated in: § RNA-seq and analysis · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataRT-qPCR results were derived from three experiments and ChIP-qPCR from two replicates.
“RT-qPCR results were calculated as mean ± SEM or mean (SD) derived from three experiments and two replicates were used for ChIP-qPCR.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The mechanism by which H3K4me1 is established and maintained at enhancers in connection with transcription factors is unknown.
“How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown.”
The paper relies on this without support.
The reduction in H3K4me1 and H3K27ac at HBRs after HNF4A loss is a direct consequence of losing HNF4A at those regions, rather than a secondary effect of altered hepatocyte identity or viability.
“suggesting that HNF4A is required to maintain H3K4me1 at HBRs.”
The paper relies on this without support.
Precise mapping of enhancers to genes is often inaccurate.
“It is difficult to correlate the expression of single genes to specific enhancers as precise mapping of enhancers to genes is often inaccurate.”
The paper relies on this without support.
Most genes are regulated by multiple enhancers because redundancy is built into gene regulatory mechanisms.
“Also, most genes are regulated by multiple enhancers since redundancy is built into gene regulatory mechanisms.”
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Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application
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Written in development and lost in ageing: the grammar of cellular identity
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- Authors
- Thakur, A., Park, K., Cullum, R., Fuglerud, B. M., Khoshnoodi, M., Drissler, S., Stephan, T. L., Lotto, J., Kim, D., Gonzalez, F. J., & Hoodless, P. A.
- Affiliations
- BC Cancer Agency (CA)
- National Cancer Institute (US)
- Corresponding author
- Hoodless, Pamela A.
- ORCID
- Venue
- Communications Biology
- Published
- 2024-01-31
- Volume
- 7
- Issue
- 1
- Pages
- 144-144
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC10830483
- OpenAlex
- W4391383020
- Cited by
- 10
- References
- 87
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 1
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Gouvernement du Canada | Canadian Institutes of Health Research (FRN128092)
- Genome British Columbia (153006)
- Michael Smith Foundation for Health Research
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (Intramural Research Program)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- HNF4α, H3K4me1, enhancers, chromatin accessibility, H3K27ac, histone modifications, transcriptional regulation, epigenetic regulation, transcription factor binding, liver
- MeSH terms
- Animals, Chromatin, Enhancer Elements, Genetic, Histones, Leukemia, Mammals, Histone-Lysine N-Methyltransferase
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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