Bröske Ann-Marie, Vockentanz Lena, Kharazi Shabnam, Huska Matthew R, Mancini Elena, Scheller Marina, Kuhl Christiane, Enns Andreas, Prinz Marco, Jaenisch Rudolf, Nerlov Claus, Leutz Achim, Andrade-Navarro Miguel A, Jacobsen Sten Eirik W, Rosenbauer Frank
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Nat Genet. 2009 Nov;41(11):1207-15. doi: 10.1038/ng.463. Epub 2009 Oct 4.
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.
DNA甲基化是一种动态的表观遗传标记，在自我更新干细胞分化过程中会发生广泛变化。然而，这些变化是干细胞命运的原因还是结果仍不清楚。在这里，我们表明造血干细胞（HSC）的替代功能程序受甲基化水平的逐渐差异支配。组成性甲基化对HSC自我更新至关重要，但对归巢、细胞周期控制和细胞凋亡抑制则是可有可无的。值得注意的是，DNA甲基转移酶1活性降低的小鼠的HSC不能抑制关键的髓系红细胞调节因子，因此可以分化为髓系红细胞后代，但不能分化为淋巴系后代。类似的甲基化剂量效应控制白血病中的干细胞功能。这些数据确定DNA甲基化是一种重要的表观遗传机制，可保护干细胞免于主要分化程序的过早激活，并表明甲基化动力学决定了组织稳态和癌症中的干细胞功能。
