DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
Abstract
DNA methylation is a dynamic epigenetic mark that undergoes extensive changes during differentiation of self-renewing stem cells. However, whether these changes are the cause or consequence of stem cell fate remains unknown. Here, we show that alternative functional programs of hematopoietic stem cells (HSCs) are governed by gradual differences in methylation levels. Constitutive methylation is essential for HSC self-renewal but dispensable for homing, cell cycle control and suppression of apoptosis. Notably, HSCs from mice with reduced DNA methyltransferase 1 activity cannot suppress key myeloerythroid regulators and thus can differentiate into myeloerythroid, but not lymphoid, progeny. A similar methylation dosage effect controls stem cell function in leukemia. These data identify DNA methylation as an essential epigenetic mechanism to protect stem cells from premature activation of predominant differentiation programs and suggest that methylation dynamics determine stem cell functions in tissue homeostasis and cancer.
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Mice with hypomorphic DNMT1 expression have relatively normal myeloerythroid potential but a significant block in lymphoid development.
“mice with hypomorphic expression of DNMT1 exhibit relatively normal myeloerythroid potential but show a significant block in lymphoid development (92).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [92]
Depletion of DNMT1 by genetic methods or by repurposing of the clinically available drug decitabine restored expression of late differentiation genes and progressive maturation even in p53/p16-null leukemia cells resistant to standard apoptosis-based therapy.
“depletion of DNMT1 by genetic methods (34”
From Runx1 regulation of Pu.1 corepressor/coactivator exchange identifies specific molecular targets for leukemia differentiation therapy (2014) · cites this paper as [34]
Decitabine maintains or increases normal HSC self-renewal, whereas it induces terminal differentiation of AML primary cells and cell lines.
“The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells.”
From CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors (2012) · cites this paper as [14]
In normal hematopoietic stem cells, which do not express high levels of lineage-specifying TF, DNMT1 depletion prevents repression of stem cell genes by differentiation stimuli, maintaining stem cell phenotype.
“In contrast, in normal HSC which do not express high levels of lineage-specifying TF, DNMT1 depletion prevents stem cell gene repression by differentiation stimuli, thereby maintaining stem cell phenotype (6–15).”
From CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors (2012) · cites this paper as [14]
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- Authors
- Bröske, A.-M., Vockentanz, L., Kharazi, S., Huska, M. R., Mancini, E., Scheller, M., Kuhl, C., Enns, A., Prinz, M., Jaenisch, R., Nerlov, C., Leutz, A., Andrade-Navarro, M. A., Jacobsen, S. E. W., & Rosenbauer, F.
- Affiliations
- Max Delbrück Center (DE)
- Lund University (SE)
- European Molecular Biology Laboratory (IT)
- University of Freiburg (DE)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Rosenbauer, Frank
- ORCID
- Venue
- Nature Genetics
- Published
- 2009-10-04
- Volume
- 41
- Issue
- 11
- Pages
- 1207-1215
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2167319166
- Cited by
- 478
- References
- 50
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 16 · 2022: 19 · 2021: 28 · 2020: 28 · 2019: 20 · 2018: 22 · 2017: 31 · 2016: 38 · 2015: 37 · 2014: 51 · 2013: 42 · 2012: 38
- FWCI
- 22.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- DNA methylation, hematopoietic stem cells, lymphoid differentiation, DNMT1, stem cell self-renewal, leukemia, cell cycle regulation, apoptosis inhibition, stem cell homing
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Animals, Cell Differentiation, Cell Survival, DNA (Cytosine-5-)-Methyltransferases, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Leukemia, Neoplastic Stem Cells, Cell Lineage, DNA Methylation, Multipotent Stem Cells, Erythroid Cells, Epigenesis, Genetic, Mice
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