清华大学颉伟研究团队发现，NR5A2将全能胚胎中的合子基因组激活与第一次谱系分化联系起来。该研究于2023年11月7日在线发表于国际一流学术期刊《细胞研究》。

据研究人员介绍，合子基因组激活（ZGA）标志着全能胚胎胚胎程序的开始，它产生了内细胞团（ICM），多能上胚层和胚外滋养层由此产生。然而，ZGA如何与哺乳动物胚胎的第一次谱系分化联系在一起仍是个谜。

研究人员报道了核受体（NR）转录因子（TF）的作用，在小鼠胚胎的2细胞（2C）至8细胞（8C）阶段，这些转录因子的基序高度富集且可及。研究人员发现，在ZGA作用下被强烈诱导的NR TF NR5A2是这种连接所必需的。在Nr5a2被敲除或敲除后，胚胎发育到2C期后正常，子代基因组基本被激活。然而，4-8C特异性基因激活严重受损，Nr5a2缺陷的胚胎随后停滞在桑椹胚期。全基因组染色质结合分析表明，NR5A2结合的顺式调控元件在2C和8C胚胎中都强烈富集于其结合基序嵌入的B1元件。在2C胚胎中，NR5A2对其结合位点的全局开放不是必需的，但对其8C特异性结合位点的开放却是必不可少的。这些8C特异性结合位点（而非2C特异性结合位点）富集在涉及胚泡和干细胞调控的基因附近，并且经常与囊胚和胚胎干细胞（ESC）中的核心多能TF结合。

重要的是，NR5A2在8C阶段调控关键的多能基因Nanog和Pou5f1/Oct4、包括Gata6在内的原始内胚层调控基因以及包括Tead4和Gata3在内的关键滋养层调控基因。与此相反，多能性核心控因子NANOG、SOX2和OCT4在小鼠ESC中同时靶向早期和晚期ICM基因。综上所述，这些数据确定了NR5A2是全能胚胎中的一个关键调节因子，它是ZGA与小鼠早期发育过程中第一次谱系分化的桥梁。

附：英文原文

Title: NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos

Author: Lai, Fangnong, Li, Lijia, Hu, Xiaoyu, Liu, Bofeng, Zhu, Ziqi, Liu, Ling, Fan, Qiang, Tian, Huabin, Xu, Kai, Lu, Xukun, Li, Qing, Feng, Kong, Wang, Lijuan, Lin, Zili, Deng, Hongyu, Li, Jinsong, Xie, Wei

Issue&Volume: 2023-11-07

Abstract: Zygotic genome activation (ZGA) marks the beginning of the embryonic program for a totipotent embryo, which gives rise to the inner cell mass (ICM) where pluripotent epiblast arises, and extraembryonic trophectoderm. However, how ZGA is connected to the first lineage segregation in mammalian embryos remains elusive. Here, we investigated the role of nuclear receptor (NR) transcription factors (TFs), whose motifs are highly enriched and accessible from the 2-cell (2C) to 8-cell (8C) stages in mouse embryos. We found that NR5A2, an NR TF strongly induced upon ZGA, was required for this connection. Upon Nr5a2 knockdown or knockout, embryos developed beyond 2C normally with the zygotic genome largely activated. However, 4–8C-specific gene activation was substantially impaired and Nr5a2-deficient embryos subsequently arrested at the morula stage. Genome-wide chromatin binding analysis showed that NR5A2-bound cis-regulatory elements in both 2C and 8C embryos are strongly enriched for B1 elements where its binding motif is embedded. NR5A2 was not required for the global opening of its binding sites in 2C embryos but was essential to the opening of its 8C-specific binding sites. These 8C-specific, but not 2C-specific, binding sites are enriched near genes involved in blastocyst and stem cell regulation, and are often bound by master pluripotency TFs in blastocysts and embryonic stem cells (ESCs). Importantly, NR5A2 regulated key pluripotency genes Nanog and Pou5f1/Oct4, and primitive endoderm regulatory genes including Gata6 among many early ICM genes, as well as key trophectoderm regulatory genes including Tead4 and Gata3 at the 8C stage. By contrast, master pluripotency TFs NANOG, SOX2, and OCT4 targeted both early and late ICM genes in mouse ESCs. Taken together, these data identify NR5A2 as a key regulator in totipotent embryos that bridges ZGA to the first lineage segregation during mouse early development.

DOI: 10.1038/s41422-023-00887-z

Source: https://www.nature.com/articles/s41422-023-00887-z