Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
The Novo Nordisk Foundation for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nat Commun. 2021 May 24;12(1):3034. doi: 10.1038/s41467-021-23308-4.
Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigenetic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together, our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.
解析控制多能性基础状态的机制是理解胚胎发育的关键。尽管如此，基础状态下的小鼠胚胎干细胞（mESC）的表观遗传调控仍未完全阐明。在这里，我们鉴定出表观遗传蛋白 MPP8 对于基础状态下的多能性是必不可少的。其耗竭会导致细胞周期停滞和自发分化。MPP8 被认为通过招募人类沉默中心（HUSH）复合物到富含 H3K9me3 的区域来抑制 LINE1 元件。出乎意料的是，我们发现缺乏染色质结构域的 MPP8 可以有效地抑制 LINE1 元件，而未注释的 C 末端对于其功能是必需的。此外，我们表明 SETDB1 将 MPP8 招募到其基因组靶位，而 LINE1 元件的转录抑制在不保留 H3K9me3 水平的情况下得以维持。总之，我们的研究结果表明，MPP8 通过与 HUSH 核心复合物的关联来保护 DNA 低甲基化的多能性基础状态，但不依赖于可检测的染色质结合和 H3K9me3 的维持。
