Volume 33, No 12, Dec 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 12, December 2023: 952-966   |  Open Access

ORIGINAL ARTICLES

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

Fangnong Lai^1,2,† , Lijia Li^1,2,† , Xiaoyu Hu^1,2,† , Bofeng Liu^1,2,† , Ziqi Zhu^1,2 , Ling Liu^1,2 , Qiang Fan^1,2 , Huabin Tian³ , Kai Xu^1,2 , Xukun Lu^1,2 , Qing Li⁴ , Kong Feng^1,2 , Lijuan Wang^1,2 , Zili Lin⁵ , Hongyu Deng³ , Jinsong Li⁴ , Wei Xie^1,2,*

¹Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China
²Tsinghua-Peking Center for Life Sciences, Beijing, China
³CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
⁴State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
⁵College of Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
^†These authors contributed equally: Fangnong Lai, Lijia Li, Xiaoyu Hu, Bofeng Liu
Correspondence: Wei Xie(xiewei121@tsinghua.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00887-z

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