ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation
Open accessAbstract
Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood. Here we employ global analyses of the mouse liver transcriptome to demonstrate that postnatal remodelling of the liver is accompanied by large-scale transcriptional and post-transcriptional transitions that are cell-type-specific and temporally coordinated. Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of ∼20% of splice isoforms in mouse and human hepatocytes. The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes. We further demonstrate that forced expression of ESRP2 in immature mouse and human hepatocytes is sufficient to drive a reciprocal shift in splicing and causes various physiological abnormalities. These findings define a direct role for ESRP2 in the generation of conserved repertoires of adult splice isoforms that facilitate terminal differentiation and maturation of hepatocytes.
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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.”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bhate et al. 2015
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 measuredWhether 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).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bhate et al. 2015
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 measuredNumerous 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).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bhate et al. 2015
Sequential 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).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bhate et al. 2015
ESRP2 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).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bhate et al. 2015
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Cites
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ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation
Bangru, S., Chen, J., Baker, N., Das, D., Chembazhi, U. V., Derham, J. M., Chorghade, S., Arif, W., Alencastro, F., Duncan, A. W., et al. (2025) · Genes & Development · doi:10.1101/gad.352129.124 · Cited by 4 · see citing works
Self-citation
- Authors
- Bhate, A., Parker, D. J., Bebee, T. W., Ahn, J., Arif, W., Rashan, E. H., Chorghade, S., Chau, A., Lee, J.-H., Anakk, S., Carstens, R. P., Xiao, X., & Kalsotra, A.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- University of Pennsylvania (US)
- University of California, Los Angeles (US)
- Corresponding author
- Kalsotra, Auinash
- ORCID
- Venue
- Nature Communications
- Published
- 2015-11-04
- Volume
- 6
- Issue
- 1
- Pages
- 8768-8768
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4635967
- OpenAlex
- W2223556930
- Cited by
- 103
- References
- 7
- Citations by year
- 2026: 1 · 2025: 13 · 2024: 12 · 2023: 11 · 2022: 7 · 2021: 12 · 2020: 13 · 2019: 9 · 2018: 11 · 2017: 10 · 2016: 4
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- March of Dimes Foundation (5-FY14-112)
- Roy J. Carver Charitable Trust (14-4335)
- University of Pennsylvania (P30 DK050306)
- National Institutes of Health (DK050306, GM088809)
- National Heart, Lung, and Blood Institute (R01HL126845)
- National Human Genome Research Institute (R01HG006264)
- National Institute of General Medical Sciences (R01GM088809)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050306)
- 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 › Cancer-related molecular mechanisms research
- Keywords
- ESRP2, alternative splicing, hepatocytes, hepatocyte differentiation, splice variants, liver transcriptome, post-transcriptional regulation, liver development
- MeSH terms
- Animals, Cell Differentiation, Humans, Immunohistochemistry, Liver, RNA Processing, Post-Transcriptional, Blotting, Western, RNA-Binding Proteins, Alternative Splicing, In Situ Hybridization, Mice, Knockout, Gene Expression Regulation, Developmental, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Mice
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