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

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.

NR5A2 gene affects the overall survival of LUAD patients by regulating the activity of CSCs through SNP pathway by OCLR algorithm and immune score

“…This study showed significant advancements and characteristics in the regulation of CSC activity by the NR5A2 gene [ [46] , [47] , [48] , [49] , [50] ]. First, we used the OCLR algorithm and immune score to fully reveal the expression pattern of NR5A2 in patients with LUAD and systematically elaborated its regulatory mechanism on CSC activity.…”

Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition

“…Nr5a2 and Esrrb together are essential for maintaining naive pluripotency in mouse embryonic stem cells 18 . Recently, Nr5a2 has been identified as a key regulator of zygotic genome activation (ZGA) in murine embryos 19 ( Nr5a2 -knockout embryos have been reported to enter arrest shortly after ZGA 20 , 21 ; however, this could be due to residual maternally deposited Nr5a2 protein in these embryos 19 ). Interestingly, Nr5a2 can replace Oct4 to potently improve the efficiency of induced reprogramming of somatic cells to pluripotency 22 .…”

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation

“…Their data showed that while Nr5a2 knockdown or knockout did not significantly impact ZGA, it led to impaired activation of 4–8 cell stage genes and resulted in embryonic arrest at the morula stage. Similarly, Festuccia et al reported that Nr5a2 knockout embryos progressed beyond the two-cell stage but exhibited significant developmental delays and morphological abnormalities at the morula stage, highlighting its crucial role in morula development and first lineage specification [ 62 , 63 ]. We hypothesize that further studies using more specific inhibitors targeting Nr5a2 or the same genetic background mice may help resolve the debates about the role of Nr5a2.5.…”