DNMT3A 对于造血干细胞的分化是必不可少的。
Dnmt3a is essential for hematopoietic stem cell differentiation.
机构信息
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.
出版信息
Nat Genet. 2011 Dec 4;44(1):23-31. doi: 10.1038/ng.1009.
Abstract
Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.
摘要
胚胎干细胞中从头 DNA 甲基转移酶 Dnmt3a 和 Dnmt3b 的缺失会阻碍分化；然而，这些酶在体干细胞中的作用在很大程度上是未知的。通过条件性缺失，我们发现 Dnmt3a 的缺失会在连续移植过程中逐渐损害造血干细胞（HSC）的分化，同时增加骨髓中的 HSC 数量。Dnmt3a 缺失的 HSCs 在不同的基因座上表现出甲基化的增加和减少，包括大量 CpG 岛超甲基化。Dnmt3a 缺失的 HSCs 上调 HSC 多能性基因并下调分化因子，其后代表现出全基因组低甲基化和 HSC 特异性基因不完全抑制。这些数据确立了 Dnmt3a 作为 HSC 调节基因表观遗传沉默的关键参与者，从而能够有效地分化。
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