Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
Cell Stem Cell. 2012 Nov 2;11(5):649-62. doi: 10.1016/j.stem.2012.08.001.
Polycomb group (PcG) proteins are key epigenetic regulators of hematopietic stem cell (HSC) fate. The PcG members Ezh2 and Ezh1 are important determinants of embryonic stem cell identity, and the transcript levels of these histone methyltransferases are inversely correlated during development. However, the role of Ezh1 in somatic stem cells is largely unknown. Here we show that Ezh1 maintains repopulating HSCs in a slow-cycling, undifferentiated state, protecting them from senescence. Ezh1 ablation induces significant loss of adult HSCs, with concomitant impairment of their self-renewal capacity due to a potent senescence response. Epigenomic and gene expression changes induced by Ezh1 deletion in senesced HSCs demonstrated that Ezh1-mediated PRC2 activity catalyzes monomethylation and dimethylation of H3K27. Deletion of Cdkn2a on the Ezh1 null background rescued HSC proliferation and survival. Our results suggest that Ezh1 is an important histone methyltransferase for HSC maintenance.
多梳抑制复合物（PcG）蛋白是造血干细胞（HSC）命运的关键表观遗传调节剂。PcG 成员 Ezh2 和 Ezh1 是胚胎干细胞特征的重要决定因素，并且在发育过程中这些组蛋白甲基转移酶的转录水平呈负相关。然而，Ezh1 在体干细胞中的作用在很大程度上是未知的。在这里，我们表明 Ezh1 使重编程的 HSCs 处于缓慢循环、未分化的状态，从而保护它们免受衰老。Ezh1 的缺失会导致大量的成体 HSCs 丢失，同时由于强烈的衰老反应，其自我更新能力也受到损害。Ezh1 缺失在衰老的 HSCs 中诱导的表观基因组和基因表达变化表明，Ezh1 介导的 PRC2 活性催化 H3K27 的单甲基化和二甲基化。在 Ezh1 缺失背景下删除 Cdkn2a 可挽救 HSC 的增殖和存活。我们的研究结果表明，Ezh1 是 HSC 维持的重要组蛋白甲基转移酶。
