DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction.
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.
Ann-Marie
AM
Bröske
Lena
L
Vockentanz
Shabnam
S
Kharazi
Matthew R
MR
Huska
Elena
E
Mancini
Marina
M
Scheller
Christiane
C
Kuhl
Andreas
A
Enns
Marco
M
Prinz
Rudolf
R
Jaenisch
Claus
C
Nerlov
Achim
A
Leutz
Miguel A
MA
Andrade-Navarro
Sten Eirik W
SE
Jacobsen
Frank
F
Rosenbauer
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006706:Homeostasis; D007938:Leukemia / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases