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.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature. 2018 May;557(7704):256-260. doi: 10.1038/s41586-018-0080-8. Epub 2018 May 2.
Upon fertilization, drastic chromatin reorganization occurs during preimplantation development . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.
受精后，在着床前胚胎发育过程中会发生剧烈的染色质重排。然而，在此期间，人类中广泛的染色质景观及其分子动力学仍在很大程度上未被探索。在这里，我们使用一种改良的转座酶可及染色质高通量测序（ATAC-seq）方法研究人类着床前胚胎发育中的染色质状态。我们发现早期人类胚胎中有广泛的可及染色质区域，这些区域与假定的顺式调控序列和转座元件广泛重叠。综合分析显示，人类和小鼠早期发育、体内多能性和人类胚胎干细胞之间的调控回路既有保守性又有差异性。此外，我们还发现广泛的开放染色质区域在合子基因组激活（ZGA）之前。可及染色质位点很容易在富含 CpG 的启动子上找到。出乎意料的是，许多其他位点位于与人类卵母细胞中 DNA 低甲基化区域重叠的远端区域，并且富含转录因子结合位点。在 ZGA 之后，这些区域中的很大一部分以转录依赖的方式变得不可访问。值得注意的是，这种广泛的染色质重排在 ZGA 期间在小鼠中是保守的，并且与非经典组蛋白标记 H3K4me3 的重编程相关，该标记与基因组沉默独特相关。总之，这些数据不仅揭示了一个保守的原则，即哺乳动物 ZGA 期间染色质转变的基础，而且有助于我们加深对人类早期发育和体外受精过程中表观遗传重编程的理解。
