In sexually reproducing organisms, life begins with the fusion of transcriptionally silent gametes, the oocyte and sperm. Although initiation of transcription in the embryo, known as zygotic genome activation (ZGA), is universally required for development, the transcription factors regulating this process are poorly conserved. In this Perspective, we discuss recent insights into the mechanisms of ZGA in totipotent mammalian embryos, namely ZGA regulation by several transcription factors, including by orphan nuclear receptors (OrphNRs) such as the pioneer transcription factor NR5A2, and by factors of the DUX, TPRX and OBOX families. We performed a meta-analysis and compiled a list of pan-ZGA genes, and found that most of these genes are indeed targets of the above transcription factors. Remarkably, more than a third of these ZGA genes appear to be regulated both by OrphNRs such as NR5A2 and by OBOX proteins, whose motifs co-occur in SINE B1 retrotransposable elements, which are enriched near ZGA genes. We propose that ZGA in mice is activated by recruitment of multiple transcription factors to SINE B1 elements that function as enhancers, and discuss a potential relevance of this mechanism to Alu retrotransposable elements in human ZGA.

在有性繁殖生物体中，生命始于转录沉默配子、卵母细胞和精子的融合。尽管胚胎中转录的启动，称为合子基因组激活 （ZGA），是发育的普遍需要，但调节这一过程的转录因子保存得很差。在这个观点中，我们讨论了对全能哺乳动物胚胎中 ZGA 机制的最新见解，即几种转录因子的 ZGA 调节，包括孤儿核受体 （OrphNRs），如先锋转录因子 NR5A2，以及 DUX、TPRX 和 OBOX 家族的因子。我们进行了荟萃分析，整理了一份 pan-ZGA 基因列表，发现这些基因中的大多数确实是上述转录因子的靶点。值得注意的是，这些 ZGA 基因中超过三分之一似乎同时受到 OrphNR（如 NR5A2）和 OBOX 蛋白的调节，其基序共出现在 SINE B1 逆转录转座因子中，这些元件在 ZGA 基因附近富集。我们提出，小鼠中的 ZGA 是通过将多个转录因子募集到作为增强子的 SINE B1 元件而被激活的，并讨论了这种机制与人类 ZGA 中 Alu 逆转录转座因子的潜在相关性。