Chromatin regulators play fundamental roles in controlling pluripotency and differentiation. We examined the effect of mutations in 703 genes from nearly 70 chromatin-modifying complexes on human embryonic stem cell (ESC) growth. While the vast majority of chromatin-associated complexes are essential for ESC growth, the only complexes that conferred growth advantage upon mutation of their members, were the repressive complexes LSD-CoREST and BHC. Both complexes include the most potent growth-restricting chromatin-related protein, ZMYM2. Interestingly, while ZMYM2 expression is rather low in human blastocysts, its expression peaks in primed ESCs and is again downregulated upon differentiation. ZMYM2-null ESCs overexpress pluripotency genes and show genome-wide promotor-localized histone H3 hyper-acetylation. These mutant cells were also refractory to differentiate in vitro and failed to produce teratomas upon injection into immunodeficient mice. Our results suggest a central role for ZMYM2 in the transcriptional regulation of the undifferentiated state and in the exit-from-pluripotency of human ESCs.

染色质调节因子在控制多能性和分化方面发挥着重要作用。我们研究了近 70 个染色质修饰复合物中 703 个基因的突变对人类胚胎干细胞 (ESC) 生长的影响。虽然绝大多数染色质相关复合物对于 ESC 生长至关重要，但唯一在其成员突变时赋予生长优势的复合物是抑制性复合物 LSD-CoREST 和 BHC。两种复合物都包含最有效的生长限制性染色质相关蛋白 ZMYM2。有趣的是，虽然ZMYM2在人类囊胚中的表达相当低，但其表达在预处理的 ESC 中达到峰值，并在分化时再次下调。ZMYM2缺失的 ESC 过度表达多能性基因，并显示全基因组启动子定位的组蛋白 H3 高度乙酰化。这些突变细胞在体外也难以分化，并且在注射到免疫缺陷小鼠体内后也无法产生畸胎瘤。我们的结果表明ZMYM2在未分化状态的转录调控和人类 ESC 多能性退出中发挥核心作用。