Zygotic genome activation by the totipotency pioneer factor Nr5a2

Abstract

Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA) in totipotent embryos. Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse embryos. Nr5a2 binds to its motif within a subtype of SINE B1/Alu transposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear family receptors. Consistent with a role in ZGA, Nr5a2 is required for progression beyond the 2-cell stage. Nr5a2 promotes chromatin accessibility during ZGA and binds to entry/exit sites of nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that distinctly regulates totipotency and pluripotency during mammalian development.One-Sentence SummaryNr5a2 is an essential pioneer transcription factor that activates expression of zygotic genes in mouse embryos.

NR5A2 connects genome activation to the first lineage segregation in early mouse development

“…Of note, a recent study reported a requirement of maternal NR5A2 in mouse ZGA and development beyond the 2C stage using a NR5A2 chemical inhibitor and Nr5a2 knockdown in oocytes. 42 By contrast, Nr5a2 KD and KO starting from the 1C stage in our experiments did not have a major impact on ZGA and 2C development. While the expression of maternal Nr5a2 is low (Fig.…”

Distinct chromatin scanning modes lead to targeting of compacted chromatin by pioneer factors FOXA1 and SOX2

“…The rewiring of genetic networks can be driven by pioneer transcription factors, which bind to active and silent chromatin regions and recruit chromatin remodelers, coactivators, or corepressor complexes to elicit gene expression changes [1][2][3] . Notably, pioneer factors enable zygotic genome activation in fruit flies 4,5 , zebrafish 6 , and mouse embryos 7 . Pioneer transcription factors characteristically have DNA binding domains compatible with recognition of DNA motifs that may only be partially exposed on the nucleosome [8][9][10] , which enables the targeting of silent chromatin with low levels of active or repressive histone marks [11][12][13] .…”

Nr5a2is essential for morula development

“…Nr5a2 KO results in global transcriptional deregulation only at the 8C-stage. Interfering with NR5A2 activity in cultured zygotes has profound consequences on ZGA and results in developmental blockade or delay starting from the 2C stage (11). However, the complete genetic loss of Nr5a2 triggers major defects only after the 8C stage.…”

“…In contrast to lineage determinants, many of which perform essential roles in the formation of the blastocyst, the invalidation of TFs involved in ZGA, including DUX, RARG, DPPA2/4, NFYA and YAP1, typically does not compromise ZGA or progression beyond the 2C stage (3)(4)(5)(6)(7)(8)(9)(10). Recently, however, the TF NR5A2 has been suggested to play a preponderant role during ZGA: upon chemical inhibition of NR5A2, developmental arrest was observed from the 2C stage (11). Even though Nr5a2 knock-out models need to be developed to formally establish its essential role during ZGA, specific TFs have been identified as regulators of the early (ZGA) and late events (lineage specification) taking place during preimplantation development.…”