Polycomb Repressive Complex 2 Proteins EZH1 and EZH2 Regulate Timing of Postnatal Hepatocyte Maturation and Fibrosis by Repressing Genes With Euchromatic Promoters in Mice
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Background & aims Little is known about mechanisms that underlie postnatal hepatocyte maturation and fibrosis at the chromatin level. We investigated the transcription of genes involved in maturation and fibrosis in postnatal hepatocytes of mice, focusing on the chromatin compaction the roles of the Polycomb repressive complex 2 histone methyltransferases EZH1 and EZH2.Methods Hepatocytes were isolated from mixed background C57BL/6J-C3H mice, as well as mice with liver-specific disruption of Ezh1 and/or Ezh2, at postnatal day 14 and 2 months after birth. Liver tissues were collected and analyzed by RNA sequencing, H3K27me3 chromatin immunoprecipitation sequencing, and sonication-resistant heterochromatin sequencing (a method to map heterochromatin and euchromatin). Liver damage was characterized by histologic analysis.Results We found more than 3000 genes differentially expressed in hepatocytes during liver maturation from postnatal day 14 to month 2 after birth. Disruption of Ezh1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and to express genes at postnatal day 14 that would normally be induced by month 2 and differentiate prematurely. Loss of Ezh1 and Ezh2 also resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive euchromatic promoters were prematurely induced in hepatocytes with loss of Ezh1 and Ezh2-these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage.Conclusions The Polycomb repressive complex 2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at euchromatic promoter regions. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate Polycomb proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.
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Other epigenetic regulators, including MECP2, EZH1/2, BRD4, SIRT1, KDM4D, and TET3, can contribute to chemically induced liver fibrosis.
“Other epigenetic regulators, such as methyl CpG binding protein 2 (MECP2), enhancer of zeste homolog 1/2 (EZH1/2), bromodomain-containing protein 4 (BRD4), Sirtuin 1 (SIRT1), lysine-specific demethylase 4D (KDM4D), and tet methylcytosine dioxygenase 3 (TET3), can contribute to chemically-induced liver fibrosis (174-178) (179, 180) (181).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [177]
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- Authors
- Grindheim, J. M., Nicetto, D., Donahue, G., & Zaret, K. S.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Zaret, Kenneth S.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 156
- Issue
- 6
- Pages
- 1834-1848
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6599454
- OpenAlex
- W2936662327
- Cited by
- 35
- References
- 79
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 2
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Gastroenterology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01GM036477)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- polycomb repressive complex 2, EZH1, EZH2, hepatocyte maturation, liver fibrosis, H3K27me3, H3K4me3, chromatin condensation, liver development, liver homeostasis
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Differentiation, Female, Gene Expression Regulation, Histones, Liver Cirrhosis, Male, Methylation, Promoter Regions, Genetic, Time Factors, Gene Expression, Euchromatin, Hepatocytes, Mice, Polycomb Repressive Complex 2, Epigenetic Repression, Gene Ontology
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