Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Nat Genet. 2019 May;51(5):844-856. doi: 10.1038/s41588-019-0398-7. Epub 2019 Apr 29.
The oocyte epigenome plays critical roles in mammalian gametogenesis and embryogenesis. Yet, how it is established remains elusive. Here, we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse oocyte epigenome. Deficiency in Setd2 leads to extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishing the correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories and aberrant acquisition of H3K4me3 at imprinting control regions instead of DNA methylation. Importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent one-cell arrest after fertilization. The preimplantation arrest is mainly due to a maternal cytosolic defect, since it can be largely rescued by normal oocyte cytosol. However, chromatin defects, including aberrant imprinting, persist in these embryos, leading to embryonic lethality after implantation. Thus, these data identify SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.
卵母细胞表观基因组在哺乳动物配子发生和胚胎发生中起着关键作用。然而，它是如何建立的仍然难以捉摸。在这里，我们报告说组蛋白赖氨酸 N-甲基转移酶 SETD2，一种 H3K36me3 甲基转移酶，是小鼠卵母细胞表观基因组的关键调节因子。Setd2 的缺乏导致卵母细胞表观基因组的广泛改变，包括 H3K36me3 的丢失、正确 DNA 甲基化组的建立失败、H3K4me3 和 H3K27me3 侵入以前的 H3K36me3 区域以及印迹控制区的 H3K4me3 异常获得而不是 DNA 甲基化。重要的是，SETD2 的母体耗竭导致卵母细胞成熟缺陷，并在受精后随后发生一细胞阻滞。着床前阻滞主要是由于母体细胞质缺陷，因为它可以通过正常卵母细胞质得到很大程度的挽救。然而，染色质缺陷，包括异常印迹，在这些胚胎中仍然存在，导致植入后胚胎致死。因此，这些数据表明 SETD2 是建立母体表观基因组的关键因子，而母体表观基因组反过来又控制胚胎发育。
