Brd4 and p300 confer transcriptional competency during zygotic genome activation

The awakening of the genome after fertilization is a cornerstone of animal development. However, the mechanisms that activate the silent genome after fertilization are poorly understood. Here, we show that transcriptional competency in zebrafish is regulated by Brd4 and p300-dependent histone acetylation. Live imaging of transcription revealed that genome activation begins at the miR-430 locus, is gradual and stochastic. We show that genome activation does not require slow-down of the cell cycle and is regulated through translation of maternally-inherited mRNAs. Among these, the enhancer regulators p300 and Brd4 can prematurely activate transcription and restore transcriptional competency when maternal mRNA translation is blocked, whereas inhibiting histone acetylation blocks genome activation. We conclude that p300 and Brd4 are sufficient to trigger genome-wide transcriptional competency by regulating histone acetylation on the first zygotic genes in zebrafish. This mechanism is critical to initiating zygotic development and developmental reprogramming.