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DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction

Broeske, Ann-Marie; Vockentanz, Lena; Kharazi, Shabnam LU ; Huska, Matthew R.; Mancini, Elena; Scheller, Marina; Kuhl, Christiane; Enns, Andreas; Prinz, Marco and Jaenisch, Rudolf, et al. (2009) In Nature Genetics 41(11). p.69-1207
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... (More)
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. (Less)
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publication status
published
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Nature Genetics
volume
41
issue
11
pages
69 - 1207
publisher
Nature Publishing Group
external identifiers
  • wos:000271247600013
  • scopus:70350654370
ISSN
1546-1718
DOI
10.1038/ng.463
language
English
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yes
id
c093a2f0-3a4e-4d9a-a502-40758b391304 (old id 1504935)
date added to LUP
2009-11-24 17:08:46
date last changed
2017-12-10 04:19:48
@article{c093a2f0-3a4e-4d9a-a502-40758b391304,
  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.},
  author       = {Broeske, Ann-Marie and Vockentanz, Lena and Kharazi, Shabnam and Huska, Matthew R. and Mancini, Elena and Scheller, Marina and Kuhl, Christiane and Enns, Andreas and Prinz, Marco and Jaenisch, Rudolf and Nerlov, Claus and Leutz, Achim and Andrade-Navarro, Miguel A. and Jacobsen, Sten Eirik W and Rosenbauer, Frank},
  issn         = {1546-1718},
  language     = {eng},
  number       = {11},
  pages        = {69--1207},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction},
  url          = {http://dx.doi.org/10.1038/ng.463},
  volume       = {41},
  year         = {2009},
}