Unexpected functions for the p300/CBP co-activator in developmental gene transcription
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The p300/CBP acetyltransferase is a conserved co-activator of gene expression that establishes H3K27 acetylation and some other histone marks. During development, the enrichment of these marks on enhancers and gene promoters is a reliable sign of gene expression, although the actual function of acetylation is unclear. We aimed to reveal p300/CBP acetylation-dependent roles in zygotic genome activation (ZGA) and development of early Drosophila melanogaster embryos. We used CRISPR/Cas9 to engineer a catalytically dead p300/CBP (nejire) allele, and studied embryos where the maternal load consists of only mutant p300/CBP. These embryos successfully developed until gastrulation, showing that ZGA appears to be largely acetylation-independent. Interestingly, whole-mount in situ hybridization revealed that whereas most genes are expressed in the embryo, some genes display consistent defective patterns, with some stripes missing while others persist. Thus, there is an enhancer-selective requirement for p300/CBP catalytic activity. Non-enzymatic functions include recruitment of RNA polymerase II to both active and some inactive promoters, which is required for Polycomb-silencing by keeping Polycomb-response elements nucleosome-free and for formation of R-loops. Our results suggest that the non-enzymatic activities of the p300/CBP co-activator are sufficient for ZGA and have been repurposed to support Polycomb-mediated silencing, revealing how chromatin regulator interplay maintains transcriptional states.