Histone H3 lysine 9 (H3K9) methylation, as a hallmark of heterochromatin, has a central role in cell lineage and fate determination. Although evidence of a cooperation between H3K9 methylation writers and their readers has started to emerge, their actual interplay remains elusive. Here, we show that loss of H3K9 methylation readers, the Hp1 family, causes reduced expression of H3K9 methyltransferases, and that this subsequently leads to the exit of embryonic stem cells (ESCs) from pluripotency and a reciprocal gain of lineage-specific characteristics. Importantly, the phenotypes of Hp1-null ESCs can be rescued by ectopic expression of Setdb1, Nanog, and Oct4. Furthermore, Setdb1 ablation results in loss of ESC identity, which is accompanied by a reduction in the expression of Hp1 genes. Together, our data support a model in which the safeguarding of ESC identity involves the cooperation between the H3K9 methylation writers and their readers.

组蛋白 H3 赖氨酸 9 (H3K9) 甲基化作为异染色质的标志，在细胞谱系和命运决定中发挥着核心作用。尽管 H3K9 甲基化作者与其读者之间合作的证据已经开始出现，但他们实际的相互作用仍然难以捉摸。在这里，我们表明，H3K9 甲基化读取器（Hp1家族）的丢失会导致 H3K9 甲基转移酶的表达减少，这随后导致胚胎干细胞（ESC）退出多能性并获得谱系特异性特征。重要的是， Hp1缺失 ESC的表型可以通过Setdb1、Nanog和Oct4的异位表达来挽救。此外，Setdb1消除会导致 ESC 身份的丧失，同时伴随着Hp1基因表达的减少。总之，我们的数据支持了一个模型，其中 ESC 身份的保护涉及 H3K9 甲基化作者与其读者之间的合作。