ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation
Open accessAbstract
Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intracellular and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of epithelial splicing regulatory protein 2 (ESRP2) stimulates processing of liver-specific microRNA ( miR-122 ) to facilitate polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein–RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq data sets, we delineated an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mouse models with miR-122 rescue experiments, we demonstrated that timed activation of ESRP2 augments the miR-122 -driven program of cytokinesis failure, ensuring the proper onset and extent of hepatocyte polyploidization.
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TL;DR
Bangru et al. identify a postnatal ESRP2–miR-122 axis that drives hepatocyte maturation and polyploidization in mouse liver. ESRP2 promotes Drosha-mediated processing of miR-122, which represses cytokinesis factors and enables binucleation and polyploidization.
Key findings
- ESRP2 protein rises post-transcriptionally during postnatal liver development: hepatic ESRP2 protein increases ~8-fold between P10 and adulthood while mRNA changes only ~1.5-fold, and ESRP2 shifts from predominantly cytoplasmic at P10 to predominantly nuclear at P21.
- ESRP2 is required for adult splicing and mature hepatocyte phenotypes: germline and acute Esrp2 deletion increase hepatocyte proliferation, reduce cell size, and reduce octaploid hepatocytes with increases in diploid/tetraploid populations; earlier-than-normal ESRP2 overexpression at P0 decreases proliferation, increases cell size, and boosts octaploid/tetraploid cells at P21.
- FLAG-ESRP2 eCLIP in hepatocytes identified 685 RefSeq genes with 90% of peaks, mostly in introns (35.9%) and 3′ UTRs (50.8%); ESRP2 preferred UG-rich motifs followed by a polyG tract spaced by 6 nt, with uridine at cross-link sites.
- ESRP2 binds the miR-122 host gene and promotes its processing: Esrp2 deletion caused accumulation of unprocessed pri-miR-122 and reduced pre-miR-122 and mature miR-122; miR-122 antagomir reversed ESRP2-driven increases in binucleate hepatocytes and restored cytokinesis factors Rhoa, Mapre1, Racgap1, and Slc25a34.
Methods
- Mouse models included germline Esrp2 KO, hepatocyte-specific acute Esrp2 deletion via AAV8-TBG-CRE in Esrp2f/f mice, Dox-inducible hepatocyte-specific ESRP2 overexpression (TRE-ESRP2;ApoE-rtTA), and CRISPR-Cas9 N-terminal 2xFLAG-ESRP2 knock-in mice for eCLIP.
- Analyses included bulk poly(A)+ RNA-seq of hepatocytes from E18, P14, adult WT, adult Esrp2 KO, and P8 ESRP2 OE livers; scRNA-seq of 12,435 liver cells yielding 10,026 hepatocytes; eCLIP-seq; polysome profiling; flow cytometry for ploidy; immunofluorescence; and primary hepatocyte culture with miR-122 mimic/antagomir.
- Differential splicing was called with rMATS using FDR < 0.10, junction counts ≥ 10, and ΔPSI ≥ 15%; differential expression used FDR < 0.05 and |log2 fold change| > 1; statistics used Welch’s t-test or one/two-way ANOVA.
Limitations
- Stated: it is unclear how ESRP2 activity differentially affects diploid versus tetraploid cells; loss of ESRP2 does not completely inhibit miR-122 production or entirely block hepatic polyploidization; whether increased polyploidy in ESRP2-expressing hepatocytes depends solely on miR-122 or also on other intermediary factors remains unresolved; ESRP2 might make the hepatic environment permissive to miR-122 without direct interaction, and future deletion of ESRP2 binding sites in the pri-miR-122 host transcript could test this.
- Stated: whether ESRP2 binding to 3′ UTRs affects transcript expression and contributes to polyploidy/maturity remains to be seen.
- Evident from the text: bulk transcriptomic analyses were performed on male mouse livers but later verified by orthogonal methods in both sexes; scRNA-seq measured only ~10% of the transcriptome and did not capture splice variants; only one-third of variably spliced events in Esrp2 KOs had a nearby binding peak, rising to 50% for cassette exons, indicating direct and indirect targets.
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Claims the paper makes
34 of 54 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Between P14 and P21, a specialized mitotic program involving programmed cytokinesis failure promotes rapid binucleation and polyploidization of hepatocytes.
“However, between P14 and P21, a specialized mitotic program involving programmed cytokinesis failure promotes rapid binucleation and polyploidization of hepatocytes (Margall-Ducos et al. 2007; Gentric and Desdouets 2014; Hsu et al. 2016).”
Quote in the paperSubstantial claim1 of 3 sources checked - Study design and conductcitation
The in vivo ESRP2-binding site determination with FLAG-ESRP2 eCLIP is accurate, as the identified UG-containing motifs match those identified in vitro by SELEX-seq and RNA bind-n-seq.
“Similar UG-containing sequence motifs for ESRP proteins have been identified in vitro by SELEX-seq (Dittmar et al. 2012) and RNA bind-n-seq (Nostrand et al. 2020), confirming the accuracy of our in vivo ESRP2-binding site determination with FLAG-ESRP2 eCLIP.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Dittmar et al. 2012 source
- cites Nostrand et al. 2020 source
The ‘In vitro RBP binding motifs’ section reports using RNA Bind-N-Seq to identify motifs for many RBPs, and ‘In vitro specificity drives in vivo binding’ discusses comparisons with eCLIP. But searches for ESRP1, ESRP2 and UG-containing ESRP motifs found no passage identifying an ESRP motif or comparing it with FLAG-ESRP2 eCLIP, so our copy cannot verify the specific match claimed. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Findingcitation
Hepatic miR-122 expression surged during the first 4 weeks of life.
“In agreement with earlier reports (Xu et al. 2010; Hsu et al. 2016), hepatic miR-122 expression surged during the first 4 weeks of life (Fig. 5B).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Xu et al. 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Hsu et al. 2016 source
- Premisecitation
miR-122 antagonizes the expression of a large proportion of hepatic mRNAs that encode for a variety of developmental, metabolic, and homeostatic functions.
“miR-122 antagonizes the expression of a large proportion of hepatic mRNAs that encode for a variety of developmental, metabolic, and homeostatic functions (Luna et al. 2017).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Luna et al. 2017 source
The Introduction (page not available) says miR-122 represses hundreds of target mRNAs and regulates transcripts involved in diverse hepatic processes, including metabolism and polyploidy; it also describes a role in hepatic homeostasis. It does not establish that those targets constitute a large proportion of all hepatic mRNAs. The Results further distinguish miR-122 binding from measurable repression of target expression. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingcitation
ESRP2 deficiency prevented the fetal-to-adult switch in splicing for hundreds of RNA transcripts that normally shift their splicing patterns in the suckling-to-weaning transition period.
“Consistent with our previous smaller-scale study (Bhate et al. 2015), ESRP2 deficiency prevented the fetal-to-adult switch in splicing for hundreds of RNA transcripts that normally shift their splicing patterns in the suckling-to-weaning transition period.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Bhate et al. 2015 source
The Results section (“ESRP2 controls postnatal hepatic AS transitions”; page unavailable) reports that adult Esrp2-knockout livers retained neonatal splicing patterns for over 96% of ESRP2-regulated events. But it tested 143 developmental events and found 31 strongly misspliced in knockouts, not hundreds of transcripts whose switch was prevented. The Discussion places many hepatocyte splicing switches in the postnatal period around the milk-to-chow transition. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
A postnatal surge in miR-122 is required for the physiological polyploidization of hepatocytes.
“This was particularly interesting because a postnatal surge in miR-122 is required for the physiological polyploidization of hepatocytes (Hsu et al. 2016; Celton-Morizur and Desdouets 2017).”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
Whether liver cells exhibit fetal or adult phenotypes is controlled by families of factors that regulate the synthesis, splicing, stability, and translation of mRNAs.
“Whether liver cells exhibit fetal or adult phenotypes is controlled by families of factors that regulate the synthesis, splicing, stability, and translation of mRNAs (Panduro et al. 1987; Bhate et al. 2015; Suzuki et al. 2019; Gong et al. 2020).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Panduro et al. 1987 source
The Conclusion (page not available) reports that gene expression changes as rat hepatocytes mature, with some genes regulated transcriptionally and others post-transcriptionally. The Discussion reports changes in apparent mRNA stability, but says the specific factors responsible for regulation are unknown; it does not establish families of factors controlling splicing or translation. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Bhate et al. 2015 source
The Results (Extensive transcriptome remodelling during liver maturation; page not provided) document changes in mRNA abundance and splicing between fetal and adult liver, and the Discussion describes transcriptional and post-transcriptional regulatory modules in hepatic development. The Discussion mentions a proposed effect of alternative polyadenylation on mRNA stability but argues against a major role for it in determining mRNA abundance during liver maturation. These passages do not establish the claim's additional point about regulation of mRNA translation. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Suzuki et al. 2019 source
The Introduction describes transcription factors regulating liver development, and the Results and Discussion link Cnot-mediated mRNA stability to postnatal liver maturation. Our copy does not establish that mRNA splicing or translation controls the fetal-versus-adult phenotype, so those parts of the attributed claim are unsupported. The supplied passages have section labels but no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
Marks of transcriptional activation H3K4me1, H3K4me3, H3K36me3, H3K27ac, and H3K9ac were largely absent over the Esrp2 gene until birth.
“Particularly, marks of transcriptional activation H3K4me1, H3K4me3, H3K36me3, H3K27ac, and H3K9ac were largely absent over the Esrp2 gene until birth (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
Hepatic ESRP2 protein levels exhibit strong upregulation (approximately eightfold) between P10 and adulthood.
“Further quantification of hepatic ESRP2 mRNA and protein levels exhibited strong upregulation in protein levels (approximately eightfold) between P10 and adulthood but showed only modest changes in RNA levels (∼1.5-fold) (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
ESRP2 is uniformly expressed in all hepatocytes across the three zones of the liver lobule.
“ESRP2 was uniformly expressed in all hepatocytes across the three zones of the liver lobule (Fig. 1F; Supplemental Fig. S1)”
Quote in the paperNot a substantial claim - Findingown data
ESRP2 signal shifted from a predominantly cytoplasmic location at P10 to a predominantly nucleoplasmic location at P21.
“similar to the immunoblot results, the ESRP2 signal shifted from a predominantly cytoplasmic location at P10 to a predominantly nucleoplasmic location at P21 (Fig. 1G).”
Quote in the paperSubstantial claim - Findingown data
ESRP2 protein expression is only detected starting around P7 in mouse liver.
“Unexpectedly, although histone modifications changed dramatically from E13.5 to P0, ESRP2 protein expression was only detected starting around P7 (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
Hepatic Esrp2 RNA levels show only modest changes (~1.5-fold) between P10 and adulthood.
“Further quantification of hepatic ESRP2 mRNA and protein levels exhibited strong upregulation in protein levels (approximately eightfold) between P10 and adulthood but showed only modest changes in RNA levels (∼1.5-fold) (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
Esrp2 mRNA shifts from the mRNP/monosome to polyribosome fractions at P7.
“Quantitative RT-PCR (qRT-PCR) analyses of fractionated lysates showed a gradual shift of Esrp2 mRNA from the mRNP/monosome to polyribosome fractions at P7 (Fig. 1D), representing increased accessibility to translational machinery occurring ∼1 week after birth.”
Quote in the paperSubstantial claim - Findingown data
The transcriptional silencing mark H3K27me3 was predominant in the embryonic stage but was replaced with activation marks in the adult liver.
“In contrast, the transcriptional silencing mark H3K27me3 was predominant in the embryonic stage but was replaced with activation marks in the adult liver.”
Quote in the paperSubstantial claim - Findingown data
Hepatocytes from P14, P21, P28, and P56 Esrp2 germline KO mice have significantly reduced cell area compared with wild-type controls.
“Liver sections immunostained with HNF4A and CTNNB1 (to mark cell boundaries) showed hepatocytes with significantly reduced cell area from P14, P21, P28, and P56 (adult) Esrp2 germline KO mice compared with those of wild-type controls (Fig. 2H,K; Supplemental Fig. S4B).”
Quote in the paperSubstantial claim - Findingown data
Regulons that are active in P14 but silenced in adult hepatocytes are less affected by ESRP2 deficiency.
“However, regulons that are active in P14 but silenced in adult hepatocytes were less affected by ESRP2 deficiency.”
Quote in the paperSubstantial claim - Findingown data
Compared with randomized sets of exons, ESRP2-regulated exons showed particular enrichment for nuclear localization signals and intrinsically unstructured polypeptide regions.
“Compared with randomized sets of exons, ESRP2-regulated exons showed particular enrichment for nuclear localization signals and intrinsically unstructured polypeptide regions (Fig. 3G).”
Quote in the paperNot a substantial claim - Findingown data
Increased hepatocyte proliferation in Esrp2 KOs was not linked to liver injury or compensatory regeneration.
“Increased hepatocyte proliferation in Esrp2 KOs was not linked to liver injury or compensatory regeneration, as histological analysis and measurement of serum ALT and AST levels showed no signs of liver damage, hepatocyte death, or inflammation (Supplemental Fig. S3A–C).”
Quote in the paperSubstantial claim - Findingown data
Almost one-third of differentially spliced mRNAs in ESRP2-deficient hepatocytes revert their splicing pattern toward the neonatal (E18) stage.
“Comparative analysis of the wild-type E18 to adult and Esrp2 KO transcriptomes revealed that almost one-third of differentially spliced mRNAs in ESRP2-deficient hepatocytes revert their splicing pattern toward the neonatal (E18) stage (Fig. 3H,I).”
Quote in the paperSubstantial claim - Findingown data
The ESRP binding motif showed a strong association with splicing transitions, particularly in the late postnatal stages.
“Among them, the ESRP binding motif showed a strong association with splicing transitions, particularly in the late postnatal stages.”
Quote in the paperSubstantial claim - Findingown data
Acute depletion of ESRP2 from adult livers led to a significant increase in the EdU-labeled hepatocyte population at 2 and 4 weeks after AAV8-TBG-CRE injections compared with AAV8-TBG-GFP controls.
“Importantly, acute depletion of ESRP2 from adult livers led to a significant increase in the EdU-labeled hepatocyte population at 2 and 4 weeks after AAV8-TBG-CRE injections compared with AAV8-TBG-GFP controls (Fig. 2M; Supplemental Fig. S5A)”
Quote in the paperSubstantial claim - Findingown data
Forced expression of ESRP2 in P6 livers resulted in a neonatal-to-adult switch in splicing for both Arhgef10l and Lsm14b.
“Remarkably, forced expression of ESRP2 in P6 livers resulted in a neonatal-to-adult switch in splicing for both Arhgef10l and Lsm14b, demonstrating that earlier than normal ESRP2 expression is sufficient to induce a premature shift in splicing of target transcripts (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data
ESRP2 deficiency resulted in a significant increase in the percentage of Ki-67+ hepatocytes.
“Furthermore, ESRP2 deficiency resulted in a significant increase in the percentage of Ki-67+ hepatocytes (Supplemental Fig. S4C).”
Quote in the paperSubstantial claim - Findingown data
In ESRP2-deficient hepatocytes, sex-dependent expression of metabolic and detoxification genes is not altered.
“The data indicated that sex-dependent expression of metabolic and detoxification genes is not altered in ESRP2-deficient hepatocytes.”
Quote in the paperNot a substantial claim - Findingown data
Most transcripts harboring ESRP2 target exons did not exhibit a significant change in their overall RNA abundance.
“These data are consistent with our observation that most transcripts harboring ESRP2 target exons did not exhibit a significant change in their overall RNA abundance (Supplemental Fig. S8B).”
Quote in the paperNot a substantial claim - Findingown data
A large but separate set of developmentally regulated events showed only a modest adult-to-neonatal splicing shift in Esrp2 KOs.
“However, a large but separate set of developmentally regulated events showed only a modest adult-to-neonatal splicing shift in Esrp2 KOs, suggesting that other factors might promote these postnatal transitions (Fig. 3H,I).”
Quote in the paperNot a substantial claim - Findingown data
Acute loss of ESRP2 from adult hepatocytes reverted the splicing of Arhgef10l and Lsm14b to neonatal patterns, similar to what was observed in the germline KOs.
“Importantly, acute loss of ESRP2 from adult hepatocytes reverted the splicing of Arhgef10l and Lsm14b to neonatal patterns, similar to what was observed in the germline KOs (Fig. 2E,G), indicating that continuous expression of ESRP2 in adulthood is necessary to maintain correct splicing patterns of target transcripts.”
Quote in the paperSubstantial claim - Findingown data
Several motifs were identified in each intronic region, including some that resemble the binding sites of known splicing factors.
“We identified several motifs in each intronic region, including some that resemble the binding sites of known splicing factors (Supplemental Fig. S10).”
Quote in the paperNot a substantial claim - Findingown data
The splicing changes in Esrp2-KO hepatocytes had minimal overlap with mRNAs regulated at the abundance levels.
“We identified 582 significantly changing splicing events within 394 genes in Esrp2-KO compared with WT adult hepatocytes, with an expected distribution of splice event type and minimal overlap with mRNAs regulated at the abundance levels (Fig. 3D).”
Quote in the paperNot a substantial claim - Findingown data
Several mature metabolic gene sets were dampened in Esrp2 KO hepatocytes, as is evident from a global shift in their pathway score distribution.
“Several mature metabolic gene sets were dampened in Esrp2 KO hepatocytes, as is evident from a global shift in their pathway score distribution (Fig. 3B; Supplemental Fig. S6F).”
Quote in the paperSubstantial claim - Findingown data
Exons reciprocally regulated in Esrp2 KO and OE data sets had the highest percentage of binding (approximately 80%).
“Of note, exons reciprocally regulated in Esrp2 KO and OE data sets had the highest percentage of binding (∼80%), providing a strong likelihood for direct regulation by ESRP2 (Fig. 4H).”
Quote in the paperNot a substantial claim - Findingown data
ESRP2 deficiency mainly affected the late set of splicing transitions.
“Consistent with the motif analysis and delayed ESRP2 expression during hepatocyte maturation, ESRP2 deficiency mainly affected the late set of splicing transitions. (Fig. 3J; Supplemental Fig. S8D).”
Quote in the paperSubstantial claim - Findingown data
At P21, only a small percentage of control hepatocytes were octaploid, whereas the majority were diploid or tetraploid.
“At P21, only a small percentage of control hepatocytes were octaploid, whereas the majority were diploid or tetraploid (Fig. 2J,N).”
Quote in the paperSubstantial claim - Findingown data
Gene sets belonging to glycolysis, gluconeogenesis, glycogen metabolism, and the pentose phosphate pathway showed the most significant decrease in Esrp2 KO hepatocytes.
“Although the gene sets belonging to glycolysis, gluconeogenesis, glycogen metabolism, and the pentose phosphate pathway showed the most significant decrease (Fig. 3B), other pathways such as fatty acid and amino acid metabolism were only slightly reduced in the Esrp2 KO hepatocytes (Supplemental Fig. S6F).”
Quote in the paperNot a substantial claim - Findingown data
ESRP2 deficiency affects the splicing of many more transcripts than it affects transcript abundance.
“ESRP2 deficiency affected the splicing of many more transcripts than abundance, indicating a more significant impact on pre-mRNA processing (Supplemental Fig. S8B).”
Quote in the paperNot a substantial claim - Findingown data
Other pathways such as fatty acid and amino acid metabolism were only slightly reduced in the Esrp2 KO hepatocytes.
“Although the gene sets belonging to glycolysis, gluconeogenesis, glycogen metabolism, and the pentose phosphate pathway showed the most significant decrease (Fig. 3B), other pathways such as fatty acid and amino acid metabolism were only slightly reduced in the Esrp2 KO hepatocytes (Supplemental Fig. S6F).”
Quote in the paperNot a substantial claim - Findingown data
The majority of ESRP2-deficient hepatocytes clustered adjacent to P14 and away from adult hepatocytes.
“The majority of ESRP2-deficient hepatocytes, however, clustered adjacent to P14 and away from adult hepatocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: ESRP2 expression in the liver is hepatocyte-specific.
- Findingown data
Esrp2 KO mice show increased hepatocyte proliferation, indicated by increased EdU labeling, relative to wild-type mice.
“We also detected a considerable increase in hepatocyte proliferation—indicated by increased 5-ethynyl-2′-deoxyuridine (EdU) labeling of new DNA synthesis and HNF4A immunostaining of liver sections—from Esrp2 KO relative to wild-type mice (Fig. 2H,L; Supplemental Fig. S4A,B).”
Quote in the paperSubstantial claim - Findingown data
No sex-specific differences in cell size and proliferation were observed between wild-type and Esrp2 KO livers.
“in our analysis, we did not observe any sex-specific differences in cell size and proliferation between wild-type and Esrp2 KO livers (Supplemental Fig. S4D,E).”
Quote in the paperNot a substantial claim - Findingown data
Robust binding clusters were detected within 500 nt upstream of and downstream from exons whose PSI values were significantly altered in Esrp2 KO hepatocytes.
“We detected robust binding clusters within 500 nt upstream of and downstream from exons whose PSI values were significantly altered in Esrp2 KO hepatocytes (Fig. 4F; Supplemental Fig. S11).”
Quote in the paperSubstantial claim - Findingown data
Earlier than normal ESRP2 expression boosted the number of octaploid and tetraploid cells in P21 livers.
“However, earlier than normal ESRP2 expression boosted the number of octaploid and tetraploid cells in P21 livers (Fig. 2J,N), indicating that premature ESRP2 activation accelerates the postnatal polyploidization of hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
In only approximately 10% of the cases, ESRP2-regulated exons were predicted to undergo nonsense-mediated decay (NMD).
“Moreover, we found that in only ∼10% of the cases, ESRP2-regulated exons were predicted to undergo nonsense-mediated decay (NMD) and thereby produce transcripts that are unproductive in terms of protein expression.”
Quote in the paperNot a substantial claim - Findingown data
Esrp2 KO hepatocytes are particularly stunted in their adult regulons (e.g., HNF4A, DBP, and CEBPA), which are typically activated during postnatal development.
“Esrp2 KO hepatocytes were particularly stunted in their adult regulons (e.g., HNF4A, DBP, and CEBPA), which are typically activated during postnatal development (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
582 significantly changing splicing events within 394 genes were identified in Esrp2-KO compared with WT adult hepatocytes.
“We identified 582 significantly changing splicing events within 394 genes in Esrp2-KO compared with WT adult hepatocytes, with an expected distribution of splice event type and minimal overlap with mRNAs regulated at the abundance levels (Fig. 3D).”
Quote in the paperSubstantial claim - Findingown data
ESRP2-regulated exons showed noticeably higher binding proportions (approximately 50%) in surrounding introns.
“ESRP2-regulated exons, which exhibited a significant PSI change in ESRP2-depleted or overexpression hepatocytes, showed noticeably higher binding proportions (∼50%) in surrounding introns.”
Quote in the paperNot a substantial claim - Findingown data
Wild-type P14 and adult hepatocytes formed distinct nonoverlapping clusters in the UMAP plot, representing stark differences in their transcriptomes.
“As expected, wild-type P14 and adult hepatocytes formed distinct nonoverlapping clusters in the UMAP plot, representing stark differences in their transcriptomes (Supplemental Fig. S6E).”
Quote in the paperNot a substantial claim- Rests on an assumption: ESRP2 expression in the liver is hepatocyte-specific.
- Findingown data
Transcripts exhibiting altered splicing patterns in ESRP2-deficient hepatocytes form highly connected networks of biological processes associated with tissue morphogenesis, cell proliferation, and EMT, with particular enrichment for molecular functions related to protein phosphorylation, cytoskeletal organization, and Rho/Ras signaling.
“We noted that the transcripts exhibiting altered splicing patterns in ESRP2-deficient hepatocytes form highly connected networks of biological processes associated with tissue morphogenesis, cell proliferation, and EMT, with particular enrichment for molecular functions related to protein phosphorylation, cytoskeletal organization, and Rho/Ras signaling (Fig. 3E).”
Quote in the paperNot a substantial claim - Findingown data
A significant downregulation of all four cytokinesis-associated factors Rhoa, Mapre1, Racgap1, and Slc25a34 was observed in ESRP2-overexpressing livers in comparison with uninduced littermate controls.
“We observed a significant downregulation of all four factors in ESRP2-overexpressing livers in comparison with uninduced littermate controls (Fig. 6C).”
Quote in the paperSubstantial claim - Findingown data
Ectopic expression of ESRP2 led to an increase in miR-122 levels in both P14 and P21 livers.
“Of note, ectopic expression of ESRP2 led to an increase in miR-122 levels in both P14 and P21 livers (Fig. 6B).”
Quote in the paperSubstantial claim - Findingreasoning
ESRP2 deficiency derepresses cytokinesis-associated factors, resulting in deficits in the temporal specification and complete polyploidization of hepatocytes.
“ESRP2 deficiency derepresses these factors, resulting in deficits in the temporal specification and complete polyploidization of hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
ESRP2 expression itself remained unchanged in the antagomir-treated cells.
“ESRP2 expression itself, however, remained unchanged in the antagomir-treated cells (Fig. 6G).”
Quote in the paperSubstantial claim - Findingown data
Starting at P14 and continuing through adulthood, ESRP2 KO livers exhibited consistently lower mature miR-122 levels relative to wild-type counterparts.
“However, starting at P14 and continuing through adulthood, ESRP2 KO livers exhibited consistently lower mature miR-122 levels relative to wild-type counterparts (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
The miR-122 mimic suppressed the expression of cytokinesis factors Rhoa, Mapre1, Racgap1, and Slc25a34.
“As anticipated, the miR-122 mimic suppressed the expression of cytokinesis factors Rhoa, Mapre1, Racgap1, and Slc25a34 (Fig. 6E,F), and miR-122-supplemented hepatocytes were enriched for binucleate cells when compared with scrambled control (Fig. 6H,I).”
Quote in the paperSubstantial claim - Findingown data
ESRP2 binds robustly to the liver-specific miR-122 host gene upstream of the region that encodes the miRNA stem-loop sequence.
“Surprisingly, we detected robust ESRP2 binding to the liver-specific miR-122 host gene upstream of the region that encodes the miRNA stem–loop sequence.”
Quote in the paperSubstantial claim - Findingown data
In vivo and primary cell culture experiments demonstrated a direct dependence of miR-122 and its gene regulatory network on ESRP2.
“Importantly, in vivo and primary cell culture experiments demonstrated a direct dependence of miR-122 and its gene regulatory network on ESRP2, indicating that timed activation of ESRP2 boosts the miR-122-driven program of cytokinesis failure and the postnatal expansion of binucleate hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
ESRP2 activity in maturing hepatocytes is synchronized through overlapping transcriptional, post-transcriptional, and subcellular localization mechanisms.
“In this study, we provide multiple lines of evidence that ESRP2 activity in maturing hepatocytes is synchronized through overlapping transcriptional, post-transcriptional, and subcellular localization mechanisms.”
Quote in the paperSubstantial claim - Findingown data
The increase in miR-122 target mRNAs in the absence of ESRP2 was particularly evident for transcripts encoding proteins involved in cell-cell junctions, cytoskeletal rearrangement, and cell division.
“This was particularly evident for transcripts encoding proteins involved in cell–cell junctions, cytoskeletal rearrangement, and cell division (Supplemental Fig. S12B).”
Quote in the paperSubstantial claim - Findingown data
In ESRP2-deficient hepatocytes, there is a selective and significant increase in the levels of miR-122 target genes, especially cytokinesis factors.
“Additional inquiry revealed that in ESRP2-deficient hepatocytes, there is a selective and significant increase in the levels of miR-122 target genes, especially cytokinesis factors.”
Quote in the paperSubstantial claim - Findingown data
ESRP2 protein abundance increases by 16-fold between P0 and P14.
“For instance, between P0 and P14, miR-122 levels increase by nearly 10-fold (Fig. 5B), whereas ESRP2 protein abundance increases by 16-fold (Fig. 1C).”
Quote in the paperNot a substantial claim - Findingown data
ESRP2 binds extensively to the miR-122 host gene transcript.
“Surprisingly, in our mapped FLAG-ESRP2 eCLIP-seq reads, we detected extensive ESRP2 binding to the miR-122 host gene transcript (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
miR-122-supplemented hepatocytes were enriched for binucleate cells when compared with scrambled control.
“As anticipated, the miR-122 mimic suppressed the expression of cytokinesis factors Rhoa, Mapre1, Racgap1, and Slc25a34 (Fig. 6E,F), and miR-122-supplemented hepatocytes were enriched for binucleate cells when compared with scrambled control (Fig. 6H,I).”
Quote in the paperSubstantial claim - Findingown data
Mature miR-122 levels closely mirror ESRP2 protein expression in the postnatal period.
“Furthermore, we noted that mature miR-122 levels closely mirror ESRP2 protein expression in the postnatal period.”
Quote in the paperSubstantial claim - Findingown data
The increased incidence of binucleation in ESRP2-expressing hepatocytes is dependent on miR-122.
“Furthermore, although we demonstrated that the increased incidence of binucleation in ESRP2-expressing hepatocytes is dependent on miR-122, loss of ESRP2 does not completely inhibit miR-122 production or entirely block hepatic polyploidization.”
Quote in the paperSubstantial claim - Findingnone given
The normal emergence of polyploid hepatocytes coincides with ESRP2 expression and its downstream RNA processing activities.
“First, the normal emergence of polyploid hepatocytes coincides with ESRP2 expression and its downstream RNA processing activities.”
Quote in the paperSubstantial claim - Findingown data
Between P0 and P14, miR-122 levels increase by nearly 10-fold.
“For instance, between P0 and P14, miR-122 levels increase by nearly 10-fold (Fig. 5B), whereas ESRP2 protein abundance increases by 16-fold (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
ESRP2 binding clusters were adjacent to the Drosha/DGCR8 cleavage site within the RNAfold-predicted secondary structure.
“These ESRP2 binding clusters (>30 reads) were adjacent to the Drosha/DGCR8 cleavage site within the RNAfold-predicted (Lorenz et al. 2011) secondary structure and likely facilitate binding to the base of the miR-122 stem loop (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
eCLIP-seq provided a network of high-confidence in vivo ESRP2-RNA interactions at single-nucleotide resolution.
“eCLIP-seq provided a network of high-confidence in vivo ESRP2–RNA interactions at single-nucleotide resolution.”
Quote in the paperSubstantial claim - Findingown data
Four distinct clusters of ESRP2 cross-linked fragments mapped to the UG-rich segments of the miR-122 host transcript both upstream of and downstream from the stem-loop region.
“Upon further analysis of eCLIP data, we noted four distinct clusters of ESRP2 cross-linked fragments that mapped to the UG-rich segments of the miR-122 host transcript both upstream of and downstream from the stem–loop region (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Integration of eCLIP-seq and RNA-seq data sets from Esrp2 KO and OE livers deconstructed the ESRP2 splicing regulatory network, revealing its direct RNA targets in hepatocytes.
“Integration of eCLIP-seq and RNA-seq data sets from Esrp2 KO and OE livers deconstructed the ESRP2 splicing regulatory network, revealing its direct RNA targets in hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
In the absence of ESRP2, the abundance of miR-122 target mRNAs increases significantly relative to nontargets.
“Our comparison of wild-type and ESRP2 KO transcriptomes indicated that in the absence of ESRP2, the abundance of miR-122 target mRNAs increases significantly relative to nontargets (Fig. 5E; Supplemental Fig. S12A).”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 is required in the genesis and maintenance of the adult transcriptome necessary for supporting the mature phenotype of hepatocytes.
“Combining single-cell and bulk hepatocyte RNA-seq analyses with targeted deletion of Esrp2 in mouse livers revealed its requirement in the genesis and maintenance of the adult transcriptome necessary for supporting the mature phenotype of hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
Developmental changes in histone modifications facilitate Esrp2 transcription, resulting in its increased mRNA expression.
“These data imply that developmental changes in histone modifications facilitate Esrp2 transcription, resulting in its increased mRNA expression.”
Quote in the paperSubstantial claim - Interpretationown data
The shift of Esrp2 mRNA to polyribosome fractions at P7 represents increased accessibility to translational machinery occurring ~1 week after birth.
“Quantitative RT-PCR (qRT-PCR) analyses of fractionated lysates showed a gradual shift of Esrp2 mRNA from the mRNP/monosome to polyribosome fractions at P7 (Fig. 1D), representing increased accessibility to translational machinery occurring ∼1 week after birth.”
Quote in the paperSubstantial claim - Interpretationown data
A temporal regulatory switch controls hepatocyte polyploidization and maturation through the activation of an RNA alternative splicing program during postnatal liver development.
“In this study, Bangru et al. describe a temporal regulatory switch that controls hepatocyte polyploidization and maturation through the activation of an RNA alternative splicing program during postnatal liver development.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 acts in a strict temporal window to activate an RNA processing program, which dictates the terminal differentiation, maturation, and polyploidization of hepatocytes.
“Thus, ESRP2 acts in a strict temporal window to activate an RNA processing program, which dictates the terminal differentiation, maturation, and polyploidization of hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 protein abundance in maturing hepatocytes is regulated post-transcriptionally at the level of either mRNA translation or protein stability (or both).
“These results suggest that ESRP2 protein abundance in maturing hepatocytes is regulated post-transcriptionally at the level of either mRNA translation or protein stability (or both).”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 stimulates the processing and optimal expression of mature miR-122.
“Specifically, we discovered robust ESRP2 binding to the miR-122 host gene transcript and showed that ESRP2 stimulates the processing and optimal expression of mature miR-122.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 regulates the processing and expression of liver-enriched miRNA miR-122 and functionally relevant mRNAs that subsequently promote cytokinesis failure and hepatocyte binucleation.
“Specifically, epithelial splicing regulatory protein 2 (ESRP2) regulates the processing and expression of liver-enriched miRNA miR-122 and functionally relevant mRNAs that subsequently promote cytokinesis failure and hepatocyte binucleation.”
Quote in the paperSubstantial claim - Interpretationown data
Exons reciprocally regulated in Esrp2 KO and OE data sets are likely directly regulated by ESRP2.
“Of note, exons reciprocally regulated in Esrp2 KO and OE data sets had the highest percentage of binding (∼80%), providing a strong likelihood for direct regulation by ESRP2 (Fig. 4H).”
Quote in the paperSubstantial claim - Interpretationown data
Premature ESRP2 activation accelerates the postnatal polyploidization of hepatocytes.
“However, earlier than normal ESRP2 expression boosted the number of octaploid and tetraploid cells in P21 livers (Fig. 2J,N), indicating that premature ESRP2 activation accelerates the postnatal polyploidization of hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
Reduced ploidy of Esrp2 KO hepatocytes is not due to their inability to synthesize DNA and/or proliferate.
“This is consistent with increased EdU labeling, indicating that reduced ploidy of Esrp2 KO hepatocytes is not due to their inability to synthesize DNA and/or proliferate.”
Quote in the paperSubstantial claim - Interpretationown data
Increased proliferation resulted directly from ESRP2 deficiency rather than indirectly from a developmental failure to exit the cell cycle.
“suggesting that increased proliferation resulted directly from ESRP2 deficiency rather than indirectly from a developmental failure to exit the cell cycle.”
Quote in the paperSubstantial claim - Interpretationown data
Continuous expression of ESRP2 in adulthood is necessary to maintain correct splicing patterns of target transcripts.
“Importantly, acute loss of ESRP2 from adult hepatocytes reverted the splicing of Arhgef10l and Lsm14b to neonatal patterns, similar to what was observed in the germline KOs (Fig. 2E,G), indicating that continuous expression of ESRP2 in adulthood is necessary to maintain correct splicing patterns of target transcripts.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 is a determinative RNA processing factor that facilitates polyploidization and maturation of hepatocytes.
“Together, these gain- and loss-of-function experiments illustrate that ESRP2 is a determinative RNA processing factor that facilitates polyploidization and maturation of hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
Despite the lack of ESRP2, a minor proportion of KO hepatocytes may still adapt to mature and support the functions of an adult liver.
“This suggests that despite the lack of ESRP2, a minor proportion of KO hepatocytes may still adapt to mature and support the functions of an adult liver.”
Quote in the paperNot a substantial claim- Rests on an assumption: ESRP2 expression in the liver is hepatocyte-specific.
- Interpretationown data
ESRP2 has a more significant impact on pre-mRNA processing than on transcript abundance.
“ESRP2 deficiency affected the splicing of many more transcripts than abundance, indicating a more significant impact on pre-mRNA processing (Supplemental Fig. S8B).”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 regulates a broad splicing program in hepatocytes via a series of primary (direct) and secondary (indirect) targets.
“Notably, the global intersection of two data sets revealed that only one-third of variably spliced events in Esrp2 KOs had a binding peak nearby, which improved to 50% if we focused on cassette exons (Fig. 4G), suggesting that ESRP2 regulates a broad splicing program in hepatocytes via a series of primary (direct) and secondary (indirect) targets.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2's temporally regulated expression ensures a timely switch in alternative splicing within maturing hepatocytes.
“These data provide compelling evidence that ESRP2 is a determinative factor required for both the genesis and maintenance of the adult hepatic splicing program and that its temporally regulated expression ensures a timely switch in alternative splicing within maturing hepatocytes.”
Quote in the paperSubstantial claim - Interpretationreasoning
ESRP2 binding clusters likely facilitate binding to the base of the miR-122 stem loop.
“These ESRP2 binding clusters (>30 reads) were adjacent to the Drosha/DGCR8 cleavage site within the RNAfold-predicted (Lorenz et al. 2011) secondary structure and likely facilitate binding to the base of the miR-122 stem loop (Fig. 5C).”
Quote in the paperNot a substantial claim - Interpretationown data
The reduction of mature miR-122 in ESRP2-deficient hepatocytes points toward a processing defect.
“Moreover, although the expression of the miR-122 nascent transcript was significantly increased, mature miR-122 levels were reduced in ESRP2-deficient hepatocytes compared with wild-type controls, pointing toward a processing defect (Fig. 5A).”
Quote in the paperSubstantial claim - Interpretationown data
An ESRP2-miR-122 axis is temporally activated in hepatocytes approximately 2 weeks after birth.
“The data presented above revealed an ESRP2–miR-122 axis that is temporally activated in hepatocytes ∼2 weeks after birth.”
Quote in the paperSubstantial claim - Interpretationown data
Earlier than normal ESRP2 activation augments the miR-122-driven program of cytokinesis failure and thereby accelerates the ploidy spectrum of hepatocytes.
“These data illustrate that earlier than normal ESRP2 activation augments the miR-122-driven program of cytokinesis failure and thereby accelerates the ploidy spectrum of hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
The nuclear activity of ESRP2 boosts miR-122 biogenesis by promoting Drosha-mediated cleavage.
“Based on the disparate expression patterns of pri-miR-122 and pre-miR-122 in ESRP2-deficient livers, we conclude that the nuclear activity of ESRP2 boosts miR-122 biogenesis by promoting Drosha-mediated cleavage.”
Quote in the paperSubstantial claim - Interpretationreasoning
Timed processing and biogenesis of miR-122 by ESRP2 repress cytokinesis-associated factors, promoting cytokinesis failure and postnatal expansion of binucleate hepatocytes.
“Fifth, timed processing and biogenesis of miR-122 by ESRP2 repress cytokinesis-associated factors, promoting cytokinesis failure and postnatal expansion of binucleate hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
Timed activation of ESRP2 boosts the miR-122-driven program of cytokinesis failure and the postnatal expansion of binucleate hepatocytes.
“indicating that timed activation of ESRP2 boosts the miR-122-driven program of cytokinesis failure and the postnatal expansion of binucleate hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 binds multiple UG-rich segments within the pri-miR-122 host transcript to stimulate DROSHA-mediated post-transcriptional processing of miR-122.
“Collectively, these results support a model in which ESRP2 binds multiple UG-rich segments within the pri-miR-122 host transcript to stimulate DROSHA-mediated post-transcriptional processing of miR-122.”
Quote in the paperSubstantial claim - Interpretationown data
miR-122 upregulation critically contributes to the ESRP2-driven increase in hepatocyte binucleation and polyploidy.
“These data demonstrate that miR-122 upregulation critically contributes to the ESRP2-driven increase in hepatocyte binucleation and polyploidy.”
Quote in the paperSubstantial claim - Interpretationown data
The ESRP2-miR-122 axis coordinates the postnatal switch from cytokinesis to endoreplication, ensuring the proper onset and extent of liver polyploidization.
“We also uncovered the ESRP2–miR-122 axis that coordinates the postnatal switch from cytokinesis to endoreplication, ensuring the proper onset and extent of liver polyploidization.”
Quote in the paperSubstantial claim - Interpretationown data
ESRP2 preferentially regulates cytokinesis by tetraploid hepatocytes.
“Our observation of drastically reduced numbers of octaploid hepatocytes in Ersp2 KOs compared with wild-type adult mice suggests that ESRP2 preferentially regulates cytokinesis by tetraploid hepatocytes.”
Quote in the paperSubstantial claim - Premisecitation
The suckling-to-weaning transition period (P14-P21 in rodents) is particularly significant for liver maturation, as hepatocyte size, ploidy, and metabolism increase markedly during this time frame.
“The suckling-to-weaning transition period (P14–P21 in rodents) is particularly significant for liver maturation, as hepatocyte size, ploidy, and metabolism increase markedly during this time frame (Margall-Ducos et al. 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Margall-Ducos et al. 2007 source
- Classified as probably not a substantial claim. 32
- May combine two claims. 57
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNumerous changes in mRNA abundance and splicing occur within the first 3 weeks of life, as hematopoiesis and proliferative activity are reduced, and gene products involved in metabolism are induced.
“Numerous changes in mRNA abundance and splicing occur within the first 3 weeks of life (Bhate et al. 2015; Chembazhi et al. 2021; Liang et al. 2022), as hematopoiesis and proliferative activity are reduced, and gene products involved in metabolism are induced (Zaret 2002; Gordillo et al. 2015).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Bhate et al. 2015 source
- cites Chembazhi et al. 2021 source
The Results section on postnatal maturation reports changes in gene expression between P14 and adult hepatocytes, supporting the mRNA-abundance portion of the cited clause. It does not establish that these changes occurred within the first three weeks of life. The Discussion describes measuring splicing within single cells as future work, rather than reporting postnatal splicing changes. The later clause about hematopoiesis and metabolism is attributed to other citations in the citing sentence. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Liang et al. 2022 source
The Results sections on hepatocyte subpopulations and transcription factors report changes in gene expression from day 1 through day 21, supporting the mRNA-abundance part of the cited clause. They do not report changes in splicing over those three weeks; the mention of a spliced mRNA describes one transcript, not a temporal change. The later claims about hematopoiesis, proliferation, and metabolism are attached to different citations in the citing sentence. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationWithin the nucleoplasm, ESRP2 displayed a punctate staining pattern that concentrated near the euchromatic and away from the heterochromatic centers.
“We further noticed that within the nucleoplasm, ESRP2 displayed a punctate staining pattern that concentrated near the euchromatic and away from the heterochromatic centers (Guenatri et al. 2004).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Guenatri et al. 2004 source
The Introduction identifies mouse chromocenters as centromeric heterochromatin clusters, and the Results describe DAPI-dense heterochromatin clusters in interphase nuclei. These passages support the reference to heterochromatic centers, but the paper does not report ESRP2 staining or its position relative to euchromatin; the citing authors present that pattern as their own observation. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMore than 95% of mouse hepatocytes at the P14 stage are diploid, and their binucleation status can be tracked over time in vitro.
“More than 95% of mouse hepatocytes at the P14 stage are diploid, and their binucleation status can be tracked over time in vitro (Hsu et al. 2016).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hsu et al. 2016 source
May combine two claims.
PremisecitationRhoa, Mapre1, Racgap1, and Slc25a34 are direct targets of miR-122 and, when depleted forcibly, cause a marked increase in binucleate hepatocytes.
“We also measured the mRNA levels of cytokinesis-associated factors Rhoa, Mapre1, Racgap1, and Slc25a34, which are direct targets of miR-122 and, when depleted forcibly, cause a marked increase in binucleate hepatocytes (Hsu et al. 2016).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hsu et al. 2016 source
The Results section identifies Rhoa, Mapre1, and Slc25a34 as direct miR-122 targets and reports increased binucleate hepatocytes after each was depleted. Racgap1 depletion also increased binucleate hepatocytes, but the paper does not identify Racgap1 as a direct target; it says Racgap1 lacks a miR-122 seed-matching sequence and is regulated via Cux1. Page numbers were not provided in the passages. (LLM, conf=0.94)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationProteins with a single RNA binding domain (RBD) are believed to interact with three to five contiguous RNA bases, whereas proteins with multiple RBDs can interact with bipartite motifs separated by one or more bases, where the two cores in bipartite motifs are bound by distinct RBDs within the same protein.
“Proteins with a single RNA binding domain (RBD) are believed to interact with three to five contiguous RNA bases, whereas proteins with multiple RBDs can interact with bipartite motifs separated by one or more bases, where the two cores in bipartite motifs are bound by distinct RBDs within the same protein (Auweter et al. 2006; Afroz et al. 2015).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe canonical microRNA biogenesis pathway involves two sequential processing events catalyzed by RNase III enzymes: Drosha/DGCR8 cleaves primary microRNA transcripts to produce precursor microRNAs, which are exported to the cytoplasm where Dicer processes them into mature microRNAs.
“The canonical microRNA biogenesis pathway involves two sequential processing events catalyzed by RNase III enzymes. In the nucleus, the microprocessor complex involving Drosha/DGCR8 cleaves primary microRNA transcripts (pri-miRs) to produce precursor microRNAs (pre-miRs), which are exported to the cytoplasm, where Dicer processes them into mature microRNAs that are eventually loaded into the RNA-”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Ha and Kim 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Shang et al. 2023 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLinear sequence motifs alone are often insufficient to fully capture the binding specificities of RBPs, and other contextual features such as RNA secondary structure and surrounding base composition contribute to binding specificity.
“Previous studies have shown that linear sequence motifs alone are often insufficient to fully capture the binding specificities of RBPs, and other contextual features such as RNA secondary structure and surrounding base composition contribute to binding specificity (Dominguez et al. 2018; Nostrand et al. 2020).”
Quote in the paperNot a substantial claim2 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe liver-enriched microRNA miR-122 is induced during postnatal development and stimulates physiological polyploidization of hepatocytes by inhibiting the expression of a set of procytokinesis targets.
“Prior studies have demonstrated that the liver-enriched microRNA miR-122 is induced during postnatal development and stimulates physiological polyploidization of hepatocytes by inhibiting the expression of a set of procytokinesis targets (Hsu et al. 2016).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hsu et al. 2016 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSequential changes in alternative splicing in the postnatal period help generate new proteoforms to support hepatocyte maturity.
“For instance, sequential changes in alternative splicing in the postnatal period help generate new proteoforms to support hepatocyte maturity (Bhate et al. 2015; Yang et al. 2023).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Bhate et al. 2015 source
- cites Yang et al. 2023
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRNA processing and miRNA-mediated gene silencing are fundamental mechanisms that fine-tune gene expression to regulate tissue development and physiology.
“RNA processing and miRNA-mediated gene silencing are fundamental mechanisms that fine-tune gene expression to regulate tissue development and physiology (Kalsotra and Cooper 2011; Baralle and Giudice 2017; Bartel 2018; Marasco and Kornblihtt 2023)”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Kalsotra and Cooper 2011 source
- cites Baralle and Giudice 2017 source
The Introduction states that alternative splicing contributes to tissue identity and organ development, supporting the RNA-processing part of the sentence. Our copy does not establish the broader claim about miRNA-mediated gene silencing; its References mention a specific miRNA that affects neuronal splicing, but not that general mechanism. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites Bartel 2018 source
Classified as probably not a substantial claim.
PremisecitationESRP2 is a key splicing factor in the liver that maintains the nonproliferative, mature phenotype of adult hepatocytes.
“ESRP2 is a key splicing factor in the liver that maintains the nonproliferative, mature phenotype of adult hepatocytes (Bhate et al. 2015).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Bhate et al. 2015 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRBPs modulate miRNA biogenesis, stability, and localization through alternative processing and/or maturation.
“or RBPs modulate miRNA biogenesis, stability, and localization through alternative processing and/or maturation (Guil and Cáceres 2007; Michlewski and Cáceres 2010, 2019; Choudhury et al. 2013; Treiber et al. 2017; Nussbacher and Yeo 2018; Yeom et al. 2018).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Guil and Cáceres 2007 source
- cites Michlewski and Cáceres 2010, 2019
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Choudhury et al. 2013 source
The Abstract (page unavailable) reports that the RNA-binding proteins MSI2 and HuR inhibit pri-miR-7 processing, producing tissue-specific differences in mature miR-7 expression. The Discussion (page unavailable) also describes processing-dependent degradation of a let-7 precursor. These passages support regulation of biogenesis and tissue-specific abundance, but do not establish that RBPs regulate the stability or localization of mature miRNAs. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFollowing injury, ESRP2 activity is transiently suppressed to activate a fetal splicing program, which attenuates Hippo signaling and facilitates liver regeneration.
“Following injury, ESRP2 activity is transiently suppressed to activate a fetal splicing program, which attenuates Hippo signaling and facilitates liver regeneration (Bangru et al. 2018).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Bangru et al. 2018 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMost epithelial tissues express both ESRP1 and ESRP2, but the liver is unique, as ESRP2 is the sole paralog present in human and mouse hepatocytes.
“Most epithelial tissues express both ESRP1 and ESRP2, but the liver is unique, as ESRP2 is the sole paralog present in human and mouse hepatocytes (Derham and Kalsotra 2023).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Derham and Kalsotra 2023 source
In “Physiological Functions of ESRPs” (page unavailable), the review says the two paralogs are typically co-expressed and that ESRP2 is the sole paralog expressed in the liver. It discusses hepatocytes and mouse experiments, but does not explicitly establish that ESRP2 is the sole paralog in both human and mouse hepatocytes. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDysregulation of RNA processing and miRNA-mediated gene silencing is associated with an increasing number of human diseases, including cancer.
“and their dysregulation is associated with an increasing number of human diseases, including cancer (Manning and Cooper 2017; Bradley and Anczuków 2023; Rogalska et al. 2023).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Manning and Cooper 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Bradley and Anczuków 2023 source
The Introduction and Abstract link dysregulated RNA splicing to cancer, describing splicing abnormalities across tumors. They do not establish the claim about miRNA-mediated gene silencing or an increasing number of human diseases; the paper focuses on splicing and cancer. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Rogalska et al. 2023
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe interplay between miRNAs and RBPs leads to global changes in gene expression in which miRNAs control expression of RBPs to regulate tissue-specific RNA processing decisions.
“The interplay between miRNAs and RBPs leads to global changes in gene expression in which miRNA(s) control expression of RBPs to regulate tissue-specific RNA processing decisions (Boutz et al. 2007; Makeyev et al. 2007; Kalsotra et al. 2010; van Kouwenhove et al. 2011; Misra et al. 2020)”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites Boutz et al. 2007 source
The Abstract (page not provided) reports that muscle-specific miR-133 reduces the splicing factor nPTB and alters splicing of several mRNAs involved in muscle maturation. This supports miRNA control of an RNA-binding protein and tissue-specific RNA processing, but the paper does not establish the claimed global changes in gene expression. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites Makeyev et al. 2007 source
- cites Kalsotra et al. 2010 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationESRPs are a conserved family of epithelial-specific RBPs that exert broad control over many physiological processes, including tissue regeneration and the epithelial-mesenchymal transition (EMT) during development and cancer progression.
“ESRPs are a conserved family of epithelial-specific RBPs that exert broad control over many physiological processes, including tissue regeneration and the epithelial–mesenchymal transition (EMT) during development and cancer progression (Warzecha et al. 2010; Lu et al. 2013; Bebee et al. 2015; Derham and Kalsotra 2023).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites Warzecha et al. 2010 source
The Introduction (page unavailable) identifies ESRP1 and ESRP2 as epithelial-specific splicing regulators and reports their downregulation during EMT; the microarray-results section calls them phylogenetically conserved splicing factors. The paper identifies hundreds of ESRP-regulated events and reports EMT-like changes after ESRP knockdown, but our copy does not establish a role for ESRPs in tissue regeneration or directly demonstrate their control of EMT during development or cancer progression. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Lu et al. 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Bebee et al. 2015 source
The Introduction describes ESRP1 and ESRP2 as epithelial-specific regulators of a genome-wide splicing program, including targets in EMT-related pathways. The Discussion describes conservation across species, and the paper supports a role in mammalian development. The passages do not establish ESRP control of tissue regeneration or cancer progression; page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataESRP2 protein abundance increased sharply in the nuclear fraction at P21, whereas cytoplasmic levels were unchanged between P10 and P21.
“Particularly, ESRP2 protein abundance increased sharply in the nuclear fraction at P21, whereas the cytoplasmic levels were unchanged between P10 and P21.”
Quote in the paperSubstantial claim- Rests on an assumption: The most striking maturational changes in the liver (both molecular and functional) happen around P14.
May combine two claims.
Findingown dataESRP2 was primarily cytoplasmic at P10 and became predominantly nuclear by P21 in hepatocytes.
“The subcellular fractionation results showed that although ESRP2 was primarily cytoplasmic at P10, it became predominantly nuclear by P21 (Fig. 1E).”
Quote in the paperSubstantial claim- Rests on an assumption: The most striking maturational changes in the liver (both molecular and functional) happen around P14.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataHepatocyte size in the acute knockouts trended lower but did not reach statistical significance.
“Hepatocyte size in the acute knockouts also trended lower but did not reach statistical significance (Supplemental Fig. S5B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataESRP2 prefers binding UG dinucleotides followed by a polyG tract spaced by 6 nt, with no preference for specific bases in the intervening spacer.
“We found that ESRP2, which contains three RRM domains (Derham and Kalsotra 2023), prefers binding UG dinucleotides followed by a polyG tract spaced by 6 nt, with no preference for specific bases in the intervening spacer (Fig. 4J).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDevelopmentally regulated events can be classified into two classes: approximately 65% undergo "early transitions" (PSI changes maximally between E18 and P14), and approximately 35% undergo "late transitions" (PSI changes maximally between P14 and adult).
“Approximately 65% of splicing events undergo “early transitions,” meaning their PSI changes maximally between E18 and P14, whereas the other class of events (∼35%) undergo “late transitions,” meaning their PSI changes maximally between P14 and adult time points (Supplemental Fig. S8C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe remaining two-thirds of mRNAs showed missplicing exclusively in the Esrp2 KO hepatocytes, as their splicing pattern was unaffected during hepatocyte maturation.
“The remaining two-thirds of mRNAs showed missplicing exclusively in the Esrp2 KO hepatocytes, as their splicing pattern was unaffected during hepatocyte maturation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataApproximately 67% of differentially spliced exons were located within the coding sequence (CDS).
“We found that ∼67% of differentially spliced exons were located within the coding sequence (CDS) (Supplemental Fig. S9).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNo differences in liver weight to body weight ratios or signs of liver damage were evident at 4 weeks after acute knockout of ESRP2.
“No differences in liver weight to body weight ratios or signs of liver damage were evident at 4 weeks after acute knockout of ESRP2 (Supplemental Fig. S5C,D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOnly a tiny fraction of wild-type adult hepatocytes was diploid, and most of the population exhibited tetraploid or octaploid DNA content.
“As expected, only a tiny fraction of wild-type adult hepatocytes was diploid, and most of the population exhibited tetraploid or octaploid DNA content (Fig. 2J,N; Supplemental Fig. S4C).”
Quote in the paperSubstantial claim- Rests on an assumption: At birth, the majority of mouse hepatocytes are diploid mononucleated cells that undergo normal cycling.
May combine two claims.
Findingown data62% of the ESRP2-regulated exons preserved the open reading frame, whereas 38% did not.
“We found that 62% of the ESRP2-regulated exons preserved the open reading frame, whereas 38% did not (Supplemental Fig. S9).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataESRP2 protein expression and the splicing pattern of ESRP2 target genes showed no evidence of sexual dimorphism.
“However, ESRP2 protein expression and the splicing pattern of ESRP2 target genes showed no evidence of sexual dimorphism (Supplemental Figs. S2D, S3D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMany ESRP2-deficient hepatocytes ordered closer to the immature P14 hepatocytes, while some Esrp2 KO hepatocytes also ordered near the wild-type adult hepatocytes along the pseudotime.
“Interestingly, although many ESRP2-deficient hepatocytes ordered closer to the immature P14 hepatocytes, some Esrp2 KO hepatocytes also ordered near the wild-type adult hepatocytes along the pseudotime.”
Quote in the paperSubstantial claim- Rests on an assumption: ESRP2 expression in the liver is hepatocyte-specific.
May combine two claims.
Findingown dataThe majority of P14 and adult hepatocytes resided on the far ends of the pseudotime trajectory; ESRP2-deficient hepatocytes occupied a position toward the middle of the maturation trajectory, forming some branches that were not populated by P14 or adult cells.
“The majority of P14 and adult hepatocytes resided on the far ends of the pseudotime trajectory; however, ESRP2-deficient hepatocytes occupied a position toward the middle of the maturation trajectory, forming some branches that were not populated by P14 or adult cells (Fig. 3A,B).”
Quote in the paperSubstantial claim- Rests on an assumption: ESRP2 expression in the liver is hepatocyte-specific.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data21 genes encoding components of cell division and/or actin cytoskeletal organization were identified among ESRP2-regulated splicing events, a subset of which is related to the NCBI MeSH terms "proto-oncogene" or "tumor suppressor".
“Further analysis of the ESRP2-regulated splicing events in hepatocytes identified 21 genes encoding components of cell division and/or actin cytoskeletal organization, a subset of which is related to the NCBI MeSH terms “proto-oncogene” or “tumor suppressor” (Fig. 3F).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataUridine was the most preferred nucleotide at the ESRP2 cross-link site and was also enriched at the flanking positions.
“Uridine was the most preferred nucleotide at the cross-link site and was also enriched at the flanking positions (Fig. 4I).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataForced expression of ESRP2 in hepatocytes of P8 livers resulted in a premature neonatal-to-adult shift in splicing of approximately 20% of the late events, a subset of which was also regulated reciprocally in the adult Esrp2 KO hepatocytes.
“Notably, forced expression of ESRP2 in hepatocytes of P8 livers resulted in a premature neonatal-to-adult shift in splicing of ∼20% of the late events, a subset of which was also regulated reciprocally in the adult Esrp2 KO hepatocytes (Fig. 3K).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEsrp2 KO livers showed a marked reduction in octaploid hepatocytes, with a concomitant increase in tetraploid and diploid hepatocytes.
“The Esrp2 KO livers, however, showed a marked reduction in octaploid hepatocytes, with a concomitant increase in tetraploid and diploid hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe de novo k-mer enrichment analysis identified UUG- and UGG-containing motifs as the top enriched sequence elements with cross-linking occurring at U residues.
“The de novo k-mer enrichment analysis identified UUG- and UGG-containing motifs as the top enriched sequence elements with cross-linking occurring at U residues.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataExons containing unstructured regions were significantly enriched for phosphorylation sites and often encoded conserved serine/threonine residues that are frequently phosphorylated in response to changes in cellular state and/or activities.
“We further noticed that the exons containing unstructured regions were significantly enriched for phosphorylation sites and often encoded conserved serine/threonine residues that are frequently phosphorylated in response to changes in cellular state and/or activities.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOnly one-third of variably spliced events in Esrp2 KOs had a binding peak nearby, which improved to 50% if focused on cassette exons.
“Notably, the global intersection of two data sets revealed that only one-third of variably spliced events in Esrp2 KOs had a binding peak nearby, which improved to 50% if we focused on cassette exons (Fig. 4G), suggesting that ESRP2 regulates a broad splicing program in hepatocytes via a series of primary (direct) and secondary (indirect) targets.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere were significantly more mononucleated to binucleated cells in the adult Esrp2 KO and fewer mononucleated to binucleated cells in the P21 ESRP2 OE livers, relative to littermate controls.
“Additionally, we counted the number of mononucleated versus binucleated hepatocytes per field and found significantly more mononucleated to binucleated cells in the adult Esrp2 KO and fewer mononucleated to binucleated cells in the P21 ESRP2 OE livers, relative to littermate controls (Supplemental Fig. S4B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataP28 Esrp2 KOs failed to undergo postnatal transitions and mimicked the wild-type P6 splicing patterns for both Arhgef10l and Lsm14b.
“The P28 Esrp2 KOs failed to undergo postnatal transitions and mimicked the wild-type P6 splicing patterns for both transcripts.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataGuanine and adenine were the second and third most common nucleotides at other positions.
“Guanine and adenine were the second and third most common nucleotides at other positions.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEarlier than normal ESRP2 activation evoked a premature decrease in hepatocyte proliferation with a simultaneous increase in cell size.
“Notably, earlier than normal ESRP2 activation evoked a premature decrease in hepatocyte proliferation with a simultaneous increase in cell size (Fig. 2I,K,L), indicating that ESRP2 promotes cell cycle exit and hypertrophic growth of hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataESRP2 binding to the intron downstream from a regulated exon was generally associated with ESRP2-mediated promotion of exon inclusion, whereas binding to the upstream intron was associated with exon skipping.
“This analysis revealed that ESRP2 binding to the intron downstream from a regulated exon was generally associated with ESRP2-mediated promotion of exon inclusion, whereas binding to the upstream intron was associated with exon skipping.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApproximately 2% of "all exons" and 5% of "all alternative exons" had ESRP2 binding in flanking introns; this increased to approximately 10% if the alternative exons were also developmentally regulated.
“Approximately 2% of “all exons” and 5% of “all alternative exons” had ESRP2 binding in flanking introns; however, this percentage increased to ∼10% if the alternative exons were also developmentally regulated (Fig. 4H).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningBoth germline depletion and acute depletion of ESRP2 from mouse livers result in reduced hepatic maturity, indicated by increased proliferation, decreased size, and a reduced ploidy spectrum of ESRP2-deficient hepatocytes.
“Second, both germline depletion and acute depletion of ESRP2 from mouse livers result in reduced hepatic maturity, indicated by increased proliferation, decreased size, and a reduced ploidy spectrum of ESRP2-deficient hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLoss of ESRP2 does not completely inhibit miR-122 production or entirely block hepatic polyploidization.
“Furthermore, although we demonstrated that the increased incidence of binucleation in ESRP2-expressing hepatocytes is dependent on miR-122, loss of ESRP2 does not completely inhibit miR-122 production or entirely block hepatic polyploidization.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEsrp2 deletion resulted in a significant accumulation of unprocessed pri-miR-122 transcripts, with a concomitant reduction in the levels of processed pre-miR-122 transcripts.
“Notably, Esrp2 deletion resulted in a significant accumulation of unprocessed pri-miR-122 transcripts, with a concomitant reduction in the levels of processed pre-miR-122 transcripts (Fig. 5D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSupplementing ESRP2-expressing hepatocytes with the miR-122 antagomir reduced miR-122 levels, restored the expression of cytokinesis factors, and reversed ESRP2-driven accumulation of binucleate cells.
“Supplementing ESRP2-expressing hepatocytes with the miR-122 antagomir not only reduced miR-122 levels but also restored the expression of cytokinesis factors and reversed ESRP2-driven accumulation of binucleate cells (Fig. 6E,F,H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA significant reduction in premature and mature miR-122 transcripts in ESRP2-deficient hepatocytes is evident only after P14, the same time frame when ESRP2 protein levels rise naturally and its localization becomes progressively nuclear.
“Also, a significant reduction in premature and mature miR-122 transcripts in ESRP2-deficient hepatocytes is evident only after P14, the same time frame when ESRP2 protein levels rise naturally and its localization becomes progressively nuclear (Figs. 1C,D, 5B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataESRP2 binds extensively to the intronic and 3′ UTR segments of RNA transcripts and prefers a bipartite motif in which the binding site is UG-rich followed by a polyG tract.
“We found that ESRP2 binds extensively to the intronic and 3′ UTR segments of RNA transcripts and prefers a bipartite motif in which the binding site is UG-rich followed by a polyG tract.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTransient induction of ESRP2 in primary cultures was sufficient to increase miR-122 levels; evoke reduction in Rhoa, Mapre1, Racgap1, and Slc25a34 mRNAs; and stimulate hepatocyte binucleation.
“Importantly, similar to the in vivo studies, transient induction of ESRP2 in primary cultures was sufficient to increase miR-122 levels; evoke reduction in Rhoa, Mapre1, Racgap1, and Slc25a34 mRNAs; and stimulate hepatocyte binucleation (Fig. 6E,F,H).”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningESRP2 is required for the genesis and maintenance of the adult liver transcriptome, including the processing and optimal expression of mature miR-122.
“Fourth, ESRP2 is required for the genesis and maintenance of the adult liver transcriptome, including the processing and optimal expression of mature miR-122.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPremature ESRP2 activation in the livers of newborn pups forces an earlier than normal onset of the adult RNA processing program, accelerating hepatocyte maturation and polyploidization.
“We also demonstrated that premature ESRP2 activation in the livers of newborn pups forces an earlier than normal onset of the adult RNA processing program, accelerating hepatocyte maturation and polyploidization.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataESRP2 deletion caused an accumulation of unprocessed primary miR-122 transcripts, with a corresponding decrease in processed pre-miR-122 and miR-122 transcripts.
“ESRP2 deletion caused an accumulation of unprocessed primary miR-122 transcripts, with a corresponding decrease in processed pre-miR-122 and miR-122 transcripts.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningEarlier than normal activation of ESRP2 in neonatal livers impedes proliferation, evokes cellular hypertrophy, and accelerates hepatocyte maturity and polyploidy.
“Third, earlier than normal activation of ESRP2 in neonatal livers impedes proliferation, evokes cellular hypertrophy, and accelerates hepatocyte maturity and polyploidy.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn ESRP2-deficient hepatocytes, the expression of the miR-122 nascent transcript was significantly increased, while mature miR-122 levels were reduced compared with wild-type controls.
“Moreover, although the expression of the miR-122 nascent transcript was significantly increased, mature miR-122 levels were reduced in ESRP2-deficient hepatocytes compared with wild-type controls, pointing toward a processing defect (Fig. 5A).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThese data highlight the multitiered control of ESRP2 expression in maturing hepatocytes, suggesting its stage-specific role in RNA processing during postnatal development.
“Collectively, these data highlight the multitiered control of ESRP2 expression in maturing hepatocytes, suggesting its stage-specific role in RNA processing during postnatal development.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEctopic expression of ESRP2 is sufficient to activate an adult gene expression program in neonatal livers, evoke premature cell cycle exit, and induce early maturation and polyploidization of hepatocytes.
“We also demonstrated that ectopic expression of ESRP2 is sufficient to activate an adult gene expression program in neonatal livers, evoke premature cell cycle exit, and induce early maturation and polyploidization of hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataFLAG-tagged ESRP2 is successfully expressed in adult transgenic mouse livers without noticeable phenotypic differences, including ESRP2 protein levels or changes in the PSI of target exons when compared with wild-type livers.
“We verified the successful expression of FLAG-tagged ESRP2 in adult transgenic mouse livers without any noticeable phenotypic differences, including ESRP2 protein levels or changes in the PSI of target exons when compared with wild-type livers (Fig. 4C).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataESRP2 promotes cell cycle exit and hypertrophic growth of hepatocytes.
“Notably, earlier than normal ESRP2 activation evoked a premature decrease in hepatocyte proliferation with a simultaneous increase in cell size (Fig. 2I,K,L), indicating that ESRP2 promotes cell cycle exit and hypertrophic growth of hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataESRP2 is a determinative factor required for both the genesis and maintenance of the adult hepatic splicing program.
“These data provide compelling evidence that ESRP2 is a determinative factor required for both the genesis and maintenance of the adult hepatic splicing program and that its temporally regulated expression ensures a timely switch in alternative splicing within maturing hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPortions of the hepatocyte transcriptome undergo dampening of the adult or reactivation of the neonatal splicing program in the absence of ESRP2.
“Thus, our global analysis revealed portions of the hepatocyte transcriptome that undergo dampening of the adult or reactivation of the neonatal splicing program in the absence of ESRP2.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataOther factors might promote the postnatal transitions of the large separate set of developmentally regulated events that show only a modest adult-to-neonatal splicing shift in Esrp2 KOs.
“However, a large but separate set of developmentally regulated events showed only a modest adult-to-neonatal splicing shift in Esrp2 KOs, suggesting that other factors might promote these postnatal transitions (Fig. 3H,I).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe lack of ESRP2 hinders the ability of hepatocytes to mature, but these hepatocytes do not regress to a completely immature fetal-like state.
“This indicates that the lack of ESRP2 hinders the ability of hepatocytes to mature, but these hepatocytes do not regress to a completely immature fetal-like state.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDuring the first 3 weeks of life, the liver transitions from an immature to a mature state as hepatocytes exit the cell cycle, become polyploid, and organize within a zonated lobular structure.
“During this period, the liver transitions from an immature to a mature state as hepatocytes exit the cell cycle, become polyploid, and organize within a zonated lobular structure (Jungermann and Kietzmann 1996; Ben-Moshe and Itzkovitz 2019; Donne et al. 2020).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar position-dependent RNA regulatory maps have been reported for other splicing regulators, which function in a cell type- or condition-specific manner.
“Similar position-dependent RNA regulatory maps have been reported for other splicing regulators, which function in a cell type- or condition-specific manner (Ule and Blencowe 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ule and Blencowe 2019 source
May combine two claims.
Interpretationown dataPosition-dependent ESRP2 binding facilitates the postnatal splicing switch for a functionally coherent set of RNAs, which supports physiological specialization and maturation of hepatocytes.
“Collectively, our integrated RNA-seq and eCLIP-seq analyses established that position-dependent ESRP2 binding facilitates the postnatal splicing switch for a functionally coherent set of RNAs, which supports physiological specialization and maturation of hepatocytes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataA programmed increase in miR-122 processing via postnatal ESRP2 activation promotes cytokinesis failure and supports diploid-to-polyploid conversion of hepatocytes.
“Based on the findings from this study, we posit a model of post-transcriptional regulatory hierarchy for liver maturation and polyploidization in which a programmed increase in miR-122 processing via postnatal ESRP2 activation promotes cytokinesis failure and supports diploid-to-polyploid conversion of hepatocytes (Fig. 7).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe post-transcriptional ESRP2-miR-122 axis is operative in vivo during a critical period of postnatal liver development and enables functional maturation and polyploidization of hepatocytes.
“Here, we identified the post-transcriptional ESRP2–miR-122 axis operative in vivo during a critical period of postnatal liver development that enables functional maturation and polyploidization of hepatocytes.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationProgrammed cytokinesis failure drives hepatocyte binucleation and polyploidy.
“Because programmed cytokinesis failure drives hepatocyte binucleation and polyploidy (Donne et al. 2020), we reasoned that ESRP2-mediated post-transcriptional processing of one or more cytokinesis effector(s) might directly contribute to postnatal polyploidization of hepatocytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Donne et al. 2020 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenBoth male and female mice were used in this study.
“Both male and female mice were used in this study.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationPersistent suppression of ESRP2 in chronic liver disease is detrimental and affects liver functioning and recovery.
“However, persistent suppression of ESRP2 in chronic liver disease is detrimental and affects liver functioning and recovery (Hyun et al. 2020, 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hyun et al. 2020, 2021
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll transcriptomic analyses were performed on samples from male mouse livers but later verified through orthogonal methods for both sexes.
“For the purposes of this study, all transcriptomic analyses were performed on samples from male mouse livers but later verified through orthogonal methods for both sexes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataSuccessful immunoprecipitation in the eCLIP procedure was validated by running a portion of IP and input samples on a gel and visualizing with an ESRP2 antibody.
“Fifteen percent of IP and input samples were run on an analytical 4%–12% PAGE gel, transferred to PVDF membrane, blocked in 5% dry milk in TBST, incubated with ESRP2 antibody (Rockland 210-301-C32), washed, incubated with HRP-conjugated antimouse secondary (Bio-Rad 1706516), and visualized with chemiluminescence imaging to validate successful IP.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe germline incorporation of the 2xFLAG tag was confirmed by Sanger sequencing of the F1 progeny.
“The germline incorporation of the 2xFLAG tag was further confirmed by Sanger sequencing of the F1 progeny.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenNational Institutes of Health (NIH) and institutional guidelines were followed in the use and care of laboratory animals, and experimental protocols were performed as approved by the IACUC at UIUC.
“National Institutes of Health (NIH) and institutional guidelines were followed in the use and care of laboratory animals, and experimental protocols were performed as approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Illinois Urbana-Champaign (UIUC).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll quantitative experiments (qRT-PCR, Western blots, and immunofluorescence) had at least three independent biological repeats.
“All quantitative experiments (qRT-PCR, Western blots, and immunofluorescence) have at least three independent biological repeats.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataEqual loading of protein samples for Western blot analysis was verified by Ponceau staining.
“Membranes were visualized for equal loading using Ponceau (PonS) staining solution (0.5% [w/v] PonS, 1% acetic acid) and then blocked using 5% milk powder (w/v) in TBST (Tris-buffered saline, 0.1% Tween 20) for 2 h at room temperature.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataeCLIP was performed on immunoprecipitations from two independent samples, each with a paired size-matched input sample before the IP washes.
“eCLIP was performed on IP from two independent samples, along with paired size-matched input before the IP washes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningAnimals were sacrificed in the morning between 0800 and 1200 h to maintain consistency in diet/fasting levels and control for circadian effects.
“For all end point tissue harvesting experiments, animals were always sacrificed in the morning between 0800 and 1200 h to maintain consistency in diet/fasting levels and control for circadian effects.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
ESRP2 expression in the liver is hepatocyte-specific.
“Because ESRP2 expression in the liver is hepatocyte-specific, we focused our analyses on hepatocyte populations.”
The paper relies on this without support.
How ESRP2 developmental expression/activity are controlled is undetermined.
“ESRP2 is a conserved RNA binding protein that activates an adult splicing program in hepatocytes (Bhate et al. 2015), but how its developmental expression/activity are controlled is undetermined.”
The paper relies on this without support.
How diverse factors cooperate to balance the ploidy and proliferation states of maturing hepatocytes is poorly understood.
“However, how these diverse factors cooperate to balance the ploidy and proliferation states of maturing hepatocytes is poorly understood.”
The paper relies on this without support.
The most striking maturational changes in the liver (both molecular and functional) happen around P14.
“We chose to conduct the ESRP2 subcellular fractionation studies at P10 and P21 because the most striking maturational changes in the liver (both molecular and functional) happen around P14.”
The paper relies on this without support.
At birth, the majority of mouse hepatocytes are diploid mononucleated cells that undergo normal cycling.
“At birth, the majority of mouse hepatocytes are diploid mononucleated cells that undergo normal cycling.”
The paper relies on this without support.
scRNA-seq measured only approximately 10% of the transcriptome and did not capture any splice variants.
“Although scRNA-seq provided critical information about the differences in hepatocyte cell states between wild-type and Esrp2 KO livers, it only measured ∼10% of the transcriptome and did not capture any splice variants.”
The paper relies on this without support.
The molecular mechanisms and upstream signals that instruct postnatal liver structural and functional transitions, including how hepatocytes exit the cell cycle, become polyploid, or acquire specialized functions, are inadequately understood.
“Crucially, the driving factors of liver maturity, such as how hepatocytes exit the cell cycle, become polyploid, or acquire specialized functions, are inadequately understood.”
The paper relies on this without support.
Most studies interrogating relationships between miRNAs and RBPs use in vitro approaches or cell culture models.
“However, most studies interrogating relationships between miRNAs and RBPs use in vitro approaches or cell culture models.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Acute ESRP2 depletion is assigned two different sampling times
MinorThe Results say the ESRP2 depletion shown in Figure 2F was evident two weeks after viral transduction, but the Figure 2 caption assigns panels F and G to four weeks after transduction.
“Robust depletion of the ESRP2 protein was evident in the adult Esrp2f/f mouse livers 2 weeks after AAV8-TBG-CRE viral vector transduction compared with AAV8-TBG-GFP controls (Fig. 2F).”
“(F,G) Western blots showing hepatic ESRP2 protein levels (F) and RT-PCR assays showing splicing patterns of ESRP2 target genes (G) following acute Esrp2 deletion (CRE) in adult (P56) livers relative to controls (GFP) at 4 weeks after viral transductions.”
Conditional allele description disagrees on which exons are floxed
MinorThe allele is described as having loxP sites around exons 3-13, but the stated downstream loxP site is after a cassette in intron 14. Those positions would place exon 14 between the loxP sites as well.
“we generated transgenic mice with loxP sites surrounding exons 3–13 of the Esrp2 gene”
“The vector featured a loxP site in intron 2 upstream of exon 3 and a neomycin selection cassette flanked by FRT sites in intron 14 followed by another loxP site.”
Primary-culture ESRP2 experiment has conflicting mouse genotypes
MinorThe Results say the cultured hepatocytes came from doxycycline-inducible ESRP2 bitransgenic mice, while the culture method says they came from wild-type C57BL/6 mice. The stated wild-type source cannot support the described doxycycline-induced transgenic ESRP2 experiment.
“we first prepared primary hepatocyte cultures from P14 TRE-ESRP2;ApoE-rtTA bitransgenic mouse livers and exposed them to either vehicle or Dox-containing mitogenic growth media (Fig. 6D).”
“Briefly, hepatocytes from wild-type P14–P15 C57BL/6 mice were seeded at a density of 40,000–50,000 per well in 24 -well Primaria cell culture plates (Corning) in growth media”
ESRP2 antibody identifiers disagree
MinorTable 1 and the eCLIP method give different Rockland identifiers for the ESRP2 antibody.
“| ESRP2, mouse, primary | Rockland | 210-301-C31 |”
“incubated with ESRP2 antibody (Rockland 210-301-C32)”
Claim that all study mice carried both overexpression transgenes conflicts with other mouse models
MinorThe mouse-model method says all mice in the study were offspring of the two overexpression lines and hemizygous for both transgenes, but the study also reports mice carrying a germline Esrp2 knockout. The universal genotype statement is incompatible with that separately described model.
“All mice reported in this study were F1 progeny of TRE-ESRP2 and ApoE-rtTA transgenic mouse matings and always hemizygous for both transgenes and the ApoE-rtTA transgene.”
“In the first model, the Esrp2 gene was deleted in the mouse germline, resulting in a constitutive whole-body knockout (KO) (Fig. 2A).”
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“It is believed that polyploidization serves as a means to gain specialized functions, boost hepatic gene expression for higher metabolic activity, and provide extra genome copies to buffer against genotoxic damage (Zhang et al. 2018; Wilkinson et al. 2019; Wilson and Duncan 2023).”
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“…extracellular factors have been identified that influence hepatic polyploidy, including transcription factors such as E2F1/7/8 (Chen et al. 2012; Pandit et al. 2012; Sladky et al. 2020) and cMyc (Baena et al. 2005), cell cycle regulators such as p53 (Kurinna et al. 2013) and Rb (Mayhew et al.…”
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“…Sladky et al. 2020) and cMyc (Baena et al. 2005), cell cycle regulators such as p53 (Kurinna et al. 2013) and Rb (Mayhew et al. 2005), signaling pathways such as insulin – PI3K – AKT (Celton-Morizur et al. 2009) and Hippo – Yap (Zhang et al. 2017), and microRNAs such as miR-122 (Hsu et al. 2016).”
Epithelial Plasticity during Liver Injury and Regeneration
Gadd, V. L., Aleksieva, N., & Forbes, S. J. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.08.016 · Cited by 142 · see citing works
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Self-citationThe Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice
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Self-citationSystematic Discovery of RNA Binding Proteins that Regulate MicroRNA Levels
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MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development
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Self-citationHepatic transcriptional responses to fasting and feeding
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Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics
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Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease
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One, Two, Three, Four! How Multiple RRMs Read the Genome Sequence
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c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver
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ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation
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Self-citationCellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A. (2021) · Genome Research · doi:10.1101/gr.267013.120 · Cited by 102 · see citing works
Self-citationLiver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy
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p53 REGULATES A MITOTIC TRANSCRIPTION PROGRAM AND DETERMINES PLOIDY IN NORMAL MOUSE LIVER
Kurinna, S., Stratton, S., Coban, Z., Schumacher, J. M., Grompe, M., Duncan, A. W., & Barton, M. (2013) · Hepatology · doi:10.1002/hep.26233 · Cited by 92 · see citing works
Self-citationCellular and Molecular Basis of Liver Development
Shin, D., & Monga, S. P. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120022 · Cited by 90 · see citing works
Splicing regulator SLU7 is essential for maintaining liver homeostasis
Elizalde, M., Urtasun, R., Azkona, M., Latasa, M. U., Goñi, S., García‐Irigoyen, O., Uriarte, I., Segura, V., Collantes, M., Scala, M. D., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74382 · Cited by 89 · see citing works
Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration
Bangru, S., Arif, W., Seimetz, J., Bhate, A., Chen, J., Rashan, E. H., Carstens, R. P., Anakk, S., & Kalsotra, A. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0129-2 · Cited by 85 · see citing works
Self-citationMicroRNA‐122 regulates polyploidization in the murine liver
Hsu, S., Delgado, E. R., Otero, P. A., Teng, K., Kutay, H., Meehan, K. M., Moroney, J. B., Monga, J. K., Hand, N. J., Friedman, J. R., et al. (2016) · Hepatology · doi:10.1002/hep.28573 · Cited by 84 · see citing works
Self-citationLuna, J. M., Barajas, J. M., Teng, K.-Y., Sun, H.-L., Moore, M. J., Rice, C. M., Darnell, R. B., & Ghoshal, K. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.025 · Cited by 80 · see citing works
Cell Maturation: Hallmarks, Triggers, and Manipulation
Alvarez-Dominguez, J., & Melton, D. (2021) · Cell · doi:10.1016/j.cell.2021.12.012 · Cited by 78 · see citing works
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Self-citationExo70 Isoform Switching upon Epithelial-Mesenchymal Transition Mediates Cancer Cell Invasion
Lu, H., Liu, J., Liu, S., Zeng, J., Ding, D., Carstens, R. P., Cong, Y., Xu, X., & Guo, W. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.10.020 · Cited by 68 · see citing works
Self-citationCellular and molecular basis of liver regeneration
Bangru, S., & Kalsotra, A. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.12.004 · Cited by 66 · see citing works
Self-citationIdentification of protein features encoded by alternative exons using Exon OntologyPreprint
Tranchevent, L.-C., Aubé, F., Dulaurier, L., Benoit‐Pilven, C., Rey, A., Poret, A., Chautard, É., Mortada, H., Desmet, F.-O., Chakrama, F. Z., et al. (2017) · Genome Research · doi:10.1101/gr.212696.116 · Cited by 64 · see citing works
Sladky, V. C., Knapp, K., Soratroi, C., Heppke, J., Eichin, F., Rocamora-Reverte, L., Szabo, T., Bongiovanni, L., Westendorp, B., Moreno, E., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2019.12.016 · Cited by 55 · see citing works
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Yeom, K., Mitchell, S. A., Linares, A. J., Zheng, S., Lin, C.-H., Wang, X., Hoffmann, A., & Black, D. L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1809609115 · Cited by 48 · see citing works
Misra, C., Bangru, S., Lin, F., Lam, K. L. H., Koenig, S. N., Lubbers, E. R., Hedhli, J., Murphy, N. P., Parker, D. J., Dobrucki, L. W., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.01.037 · Cited by 46 · see citing works
Self-citationA time-resolved multi-omic atlas of the developing mouse liverPreprint
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Hepatic immune regulation and sex disparities
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Cell-type specific polysome profiling from mammalian tissues
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Self-citationSignalling pathways and transcriptional regulators orchestrating liver development and cancer
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“This requires precise activation of transcriptional, post-transcriptional, and signaling programs to ensure proper differentiation, growth, and maturation of hepatocytes (Kyrmizi et al. 2006; Elizalde et al. 2014; Bhate et al. 2015; Campbell et al. 2021; Wesley et al. 2022).”
The discovery, function, and regulation of epithelial splicing regulatory proteins (ESRP) 1 and 2
Derham, J. M., & Kalsotra, A. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221124 · Cited by 16 · see citing works
Self-citationAn Optimized Proteomics Approach Reveals Novel Alternative Proteins in Mouse Liver Development
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The Ploidy State as a Determinant of Hepatocyte Proliferation
Wilson, S. R., & Duncan, A. W. (2023) · Seminars in liver disease (Print) · doi:10.1055/a-2211-2144 · Cited by 11 · see citing works
Self-citationLiver physiological polyploidization: MicroRNA-122 a key regulator
Celton-Morizur, S., & Desdouets, C. (2017) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2016.07.006 · Cited by 5 · see citing works
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- Authors
- Bangru, S., Chen, J., Baker, N., Das, D., Chembazhi, U. V., Derham, J. M., Chorghade, S., Arif, W., Alencastro, F., Duncan, A. W., Carstens, R. P., & Kalsotra, A.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- University of Pittsburgh (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2025-01-10
- Volume
- 39
- Issue
- 5-6
- Pages
- 325-347
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC11874994
- OpenAlex
- W4406268615
- Semantic Scholar
- 52a8e5d19b82621404a514a35796f7d4ea7dce3f
- Cited by
- 4
- References
- 99
- Citations by year
- 2026: 2 · 2025: 2
- Type
- posted content
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (R01AA010154, R01HL126845, R21HD104039, R01DK103645)
- Chan Zuckerberg Biohub Chicago Award
- Muscular Dystrophy Association (MDA1072487)
- Commonwealth of Pennsylvania
- NIH Tissue Microenvironment Training Program (T32-EB019944)
- University of Illinois Urbana-Champaign
- Scott Dissertation Completion Fellowship
- NIH Chemistry–Biology Interface Training Program (T32-GM070421)
- Herbert E. Carter Fellowship in Biochemistry
- Danica Dabich Fellowship in Biochemistry
- NIH Predoctoral National Research Service Award Fellowship (F30DK108567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- ESRP2, miR-122, hepatocyte maturation, postnatal liver development, RNA splicing regulation, microRNA biogenesis, cytokinesis failure, RNA-protein interactions
- MeSH terms
- Animals, Liver, Polyploidy, RNA-Binding Proteins, Gene Expression Regulation, Developmental, Hepatocytes, MicroRNAs, Cytokinesis, Mice
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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 2026-10-22.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.
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