Article abstract
Nature Genetics 41, 1207 - 1215 (2009)
Published online: 4 October 2009 | doi:10.1038/ng.463
DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
Ann-Marie Bröske1,7, Lena Vockentanz1,7, Shabnam Kharazi2, Matthew R Huska1, Elena Mancini3, Marina Scheller1, Christiane Kuhl1, Andreas Enns1, Marco Prinz4, Rudolf Jaenisch5, Claus Nerlov3, Achim Leutz1, Miguel A Andrade-Navarro1, Sten Eirik W Jacobsen2,6 & Frank Rosenbauer1
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.
- Max Delbrück Center for Molecular Medicine, Berlin, Germany.
- Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
- European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Italy.
- Department of Neuropathology, University of Freiburg, Freiburg, Germany.
- The Whitehead Institute, Cambridge, Massachusetts, USA.
- Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England.
- These authors contributed equally to this work.
Correspondence to: Frank Rosenbauer1 e-mail: f.rosenbauer@mdc-berlin.de
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