美国宾夕法尼亚大学Kenneth S. Zaret研究小组发现，不同的H3K9me3异染色质维持动态支配多能细胞中不同的基因程序和重复序列。该项研究成果于2024年10月31日在线发表在《自然—细胞生物学》杂志上。

研究人员工程化了Suv39h2敲除的小鼠胚胎干细胞，以在1小时内降解剩余的两个H3K9me3赖氨酸甲基转移酶（KMT），并发现被动稀释和主动去除均有助于H3K9me3的衰减，在12-24小时内。研究人员在基因组中发现四种不同的H3K9me3衰减速率，以及预测稳定性类别的染色质特征和转录因子结合模式。一个“二元开关”控制异染色质的紧缩，在KMT耗竭后，异染色质蛋白1（HP1）迅速从异染色质解离，而特定的HP1阈值水平限制了先驱因子的结合、染色质开放和在12小时内的多能性退出。意外地，退缩的H3K9me3区域揭示了富含异染色质诱导蛋白的残余HP1β峰。这些研究结果揭示了不同的H3K9me3异染色质维持动态，支配着基因网络和重复序列，这些共同保护多能性。

研究人员表示，H3K9me3异染色质由KMT建立，并由HP1亚型紧缩，抑制可变谱系基因和DNA重复序列。人们对H3K9me3异染色质稳定性的理解目前仅限于单个区域和DNA重复。

附：英文原文

Title: Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programmes and repeats in pluripotent cells

Author: Zhang, Jingchao, Donahue, Greg, Gilbert, Michael B., Lapidot, Tomer, Nicetto, Dario, Zaret, Kenneth S.

Issue&Volume: 2024-10-31

Abstract: H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12–24hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A ‘binary switch’ governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3 heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency.

DOI: 10.1038/s41556-024-01547-z

Source: https://www.nature.com/articles/s41556-024-01547-z