Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation
Abstract
Summary: Tissue generation and repair requires a stepwise process of cell fate restriction to ensure that adult stem cells differentiate in a timely and appropriate manner. A crucial role has been implicated for Polycomb-group (PcG) proteins and the H3K27me3 repressive histone mark in coordinating the transcriptional programmes necessary for this process, but the targets and developmental timing for this repression remain unclear. To address these questions, we generated novel genome-wide maps of H3K27me3 and H3K4me3 in freshly isolated muscle stem cells. These data, together with the analysis of two conditional Ezh2-null mouse strains, identified a critical proliferation phase in which Ezh2 activity is essential. Mice lacking Ezh2 in satellite cells exhibited decreased muscle growth, severely impaired regeneration and reduced stem cell number, due to a profound failure of the proliferative progenitor population to expand. Surprisingly, deletion of Ezh2 after the onset of terminal differentiation did not impede muscle repair or homeostasis. Using these knockout models and the RNA-Seq and ChIP-Seq datasets, we show that Ezh2 does not regulate the muscle differentiation process in vivo. These results emphasise the lineage and cell-type-specific functions of Ezh2 and Polycomb repressive complex 2.
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Many H3K4me3-rich genes in quiescent HFSCs or MuSCs are functionally important for activation and proliferation.
“In support of the hypothesis that the quiescent state is poised for activation, many of these H3K4me3-rich genes (most of which are expressed at low levels) are functionally important for activation and proliferation.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [62]
Many H3K4me3-rich genes in quiescent HFSCs or MuSCs are expressed at low levels.
“In support of the hypothesis that the quiescent state is poised for activation, many of these H3K4me3-rich genes (most of which are expressed at low levels) are functionally important for activation and proliferation.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [62]
Epigenetic profiling of the H3K4me3 mark in quiescent HFSCs or quiescent MuSCs has revealed a number of genes marked by this permissive histone mark.
“Epigenetic profiling of the H3K4me3 mark in quiescent HFSCs or quiescent MuSCs (T.H.C and T.A.R, unpublished observations) has revealed a number of genes that are marked by this permissive histone mark61,62.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [62]
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- Authors
- Woodhouse, S., Pugazhendhi, D., Brien, P., & Pell, J. M.
- Affiliations
- Babraham Institute (GB)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2013-01-15
- Volume
- 126
- Issue
- 2
- Pages
- 565-579
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2142632658
- Cited by
- 84
- References
- 72
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 13 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 6 · 2013: 5
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/H019243/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- EZH2, satellite cells, Polycomb group proteins, polycomb repressive complex 2, H3K27me3, H3K4me3, histone methylation, muscle regeneration, muscle growth, terminal differentiation, cell fate restriction, conditional knockout mice
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Differentiation, Male, Satellite Cells, Skeletal Muscle, Cell Growth Processes, Mice, Polycomb Repressive Complex 2
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