Mus musculus Raw sequence reads

Zygotic genome activation (ZGA), the first transcriptional event at the onset of life, is crucial for early embryonic development. However, the mechanisms that initiate and regulate ZGA in mammals remain poorly understood. In this study, we demonstrate that p300/CBP-catalyzed acetylation plays a vital role in regulating ZGA. Inhibition of p300/CBP acetyltransferase activity results in impaired minor ZGA and a subsequent 2-cell arrest. By profiling the dynamic landscape of p300 during the ZGA stage, we uncover a "three-step model" distribution of p300, akin to that of RNA polymerase II (Pol II). p300 recruits Pol II, which is pre-configured in the promoter regions of ZGA genes, and orchestrates the gradual establishment of enhancer activity during the early 2-cell stage to activate ZGA. Furthermore, p300 enhances minor ZGA by promoting the expression of DUX. Restoring DUX levels, which are diminished due to p300/CBP inhibition, rescues ZGA and embryonic development by re-establishing Pol II enrichment on minor ZGA genes. Overall, our findings elucidate the mechanism by which p300/CBP regulates ZGA through acetylation and activation of the key transcription factor DUX.