Zygotic genome activation by the totipotency pioneer factor Nr5a2 II. Zygotic genome activation by the totipotency pioneer factor Nr5a2 II

Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA). 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 2-cell embryos. Nr5a2 is required for progression beyond the 2-cell stage. It binds to its motif within SINE B1/Alu retrotransposable 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 receptors. Nr5a2 promotes chromatin accessibility during ZGA and binds nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that regulates ZGA. Overall design: Single embryo RNA seq of Nr5a2 (55) and control (57) knockdown 2C embryos.

生命起始于合子基因组激活（zygotic genome activation, ZGA）过程中遗传调控从母本基因组向胚胎基因组的转换。尽管该过程至关重要，但哺乳动物中ZGA的核心调控因子仍在很大程度上未被探明。通过从头基序搜索（de novo motif searches），我们将孤核受体（orphan nuclear receptor）Nr5a2鉴定为小鼠2细胞胚胎中主要ZGA的关键激活因子。Nr5a2是胚胎突破2细胞阶段的必需因子。它可结合ZGA基因顺式调控区域（cis-regulatory regions）内短散在核元件B1/Alu（SINE B1/Alu）逆转座元件（retrotransposable elements）中的自身识别基序。化学抑制实验显示，72%的ZGA基因受Nr5a2及其他潜在孤核受体的调控。Nr5a2可在ZGA过程中促进染色质开放，并在体外结合核小体DNA。综上，我们认为Nr5a2是调控ZGA的核心先驱因子（pioneer factor）。整体实验设计：对Nr5a2敲低组（55枚）与对照组（57枚）的2细胞胚胎开展单胚胎RNA测序（RNA-seq）。