The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion
Open accessAbstract
The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a "genetic genomics" screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress.
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Overexpression of EZH2 in HSCs prevents HSC exhaustion.
“overexpression of EZH2 in HSCs prevents HSC exhaus-tion59”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [59]
Disturbing many epigenetic writers or erasers severely impairs HSC function.
“perturbation of a large number of epigenetic writers or erasers severely affects HSC function.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [64]
In mice, altered expression of wild-type or mutant epigenetic writers affects HSC self-renewal.
“studies in mice have revealed that (enforced) altered expression of wild-type or mutant epigenetic writers affects self-renewal of HSCs.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [64]
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“Recent studies suggest that the epigenetic modifier, enhancer of zeste homolog 2 (EZH2), which catalyzes trimethylation on histone 3 at lysine 27 (H3K27me3) as a subunit of the polycomb repressive complex 2 (PRC2), prevents hematopoietic stem cell exhaustion and is critical for T cell differentiation, maintenance of T…”
Background
- Authors
- Kamminga, L. M., Bystrykh, L. V., de Boer, A., Houwer, S., Douma, J., Weersing, E., Dontje, B., & de Haan, G.
- Affiliations
- University Medical Center Groningen (NL)
- From the Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-03-01
- Volume
- 107
- Issue
- 5
- Pages
- 2170-2179
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895717
- OpenAlex
- W2138712261
- Cited by
- 376
- References
- 58
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 14 · 2021: 13 · 2020: 20 · 2019: 18 · 2018: 17 · 2017: 20 · 2016: 28 · 2015: 16 · 2014: 25 · 2013: 32 · 2012: 18
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Ministry of Earth Sciences
- Ministry of Education, India
- National Heart, Lung, and Blood Institute (R01HL073710)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- EZH2, Polycomb group proteins, hematopoietic stem cells, stem cell exhaustion, replicative stress, cellular senescence, histone methylation, chromatin modification, serial transplantation, hematopoietic recovery, mouse embryonic fibroblasts
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Division, Cell Survival, Embryo, Mammalian, Female, Fibroblasts, Hematopoietic Stem Cells, Histones, Histone-Lysine N-Methyltransferase, Protein Processing, Post-Translational, Proteins, Retroviridae, Transduction, Genetic, Bone Marrow Transplantation, Cellular Senescence, Chromatin Assembly and Disassembly, Mice, Polycomb Repressive Complex 2
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