DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
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DOI：
10.1038/ng.463
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发表时间：
2009-11-01
期刊：
影响因子：
30.8
通讯作者：
Rosenbauer, Frank
中科院分区：
文献类型：
--
作者：
Broeske, Ann-Marie;Vockentanz, Lena;Rosenbauer, Frank
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发生广泛的变化。然而，这些变化是干细胞命运的原因还是结果仍然未知。在这里，我们表明，造血干细胞（HSC）的替代功能程序是由甲基化水平的逐渐差异。组成性甲基化对于HSC自我更新是必需的，但对于归巢、细胞周期控制和凋亡抑制是不必要的。值得注意的是，来自DNA甲基转移酶1活性降低的小鼠的HSC不能抑制关键的骨髓红细胞调节因子，因此可以分化为骨髓红细胞，但不能分化为淋巴细胞后代。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甲基化是保护干细胞免受主要分化程序过早激活的重要表观遗传机制，并表明甲基化动力学决定了干细胞在组织稳态和癌症中的功能。
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.