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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We thank V. Malchin, C. Graubmann and J.F. Zinke for their excellent technical assistance; J. Schoenheit for his help with real-time PCR; H.P. Rahn and Z. Ma for assistance with high-speed cell sorting; M.L. Cleary (Stanford University School of Medicine), S. Fillatreau (Deutsches Rheuma-Forschungszentrum), A. Müller (University of Würzburg), K. Rajewsky (Harvard Medical School), M. Rehli (University of Regensburg), M. Tomasson (Washington University School of Medicine), B.L. Kee (University of Chicago) and T. Somervaille (Stanford University School of Medicine) for reagents; members of the Rosenbauer lab for discussions; D.G. Tenen for support during the initial phase of this study; and C. Plass, C. Müller-Tidow, C. Bonifer and D.G. Tenen for advice on the manuscript. This work was supported by grants from the German Research Foundation, the German Cancer Aid (Mildred Scheel) and the Helmholtz Association of German Research Centers to F.R. S.E.W.J. is the recipient of a strategic appointment grant from the UK Medical Research Council.
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Bröske, AM., Vockentanz, L., Kharazi, S. et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41, 1207–1215 (2009). https://doi.org/10.1038/ng.463
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