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.
Bröske
Ann-Marie
AM
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Vockentanz
Lena
L
Kharazi
Shabnam
S
Huska
Matthew R
MR
Mancini
Elena
E
Scheller
Marina
M
Kuhl
Christiane
C
Enns
Andreas
A
Prinz
Marco
M
Jaenisch
Rudolf
R
Nerlov
Claus
C
Leutz
Achim
A
Andrade-Navarro
Miguel A
MA
Jacobsen
Sten Eirik W
SE
Rosenbauer
Frank
F
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