Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer-factor-mediated zygotic genome activation.
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Marsh AJ, Pirogov S, Kaur Y, Ruffridge AJ, Sajwan S, Gibson TJ, Hunt G, Harrison MM, Mannervik M
Mol. Cell 85 (12) 2409-2424.e8 [2025-06-19; online 2025-05-28]
Immediately after fertilization, the genome is transcriptionally quiescent. Maternally encoded pioneer factors reprogram the chromatin state and facilitate transcription of the zygotic genome. In Drosophila, transcription is initiated by the pioneer factor Zelda. While Zelda-occupied sites are enriched with histone acetylation, a post-translational mark associated with active cis-regulatory regions, the functional relationship between Zelda and histone acetylation remained unclear. We show that Zelda-mediated recruitment of the histone acetyltransferase CREB-binding protein (CBP) is essential for zygotic transcription. CBP catalytic activity is necessary for the release of RNA polymerase II (RNA Pol II) into elongation and for embryonic development. However, CBP also activates transcription independent of acetylation through RNA Pol II recruitment. Neither CBP-mediated acetylation nor CBP itself is required for the pioneering function of Zelda. Our data suggest that pioneer-factor-mediated recruitment of CBP is a conserved mechanism required to activate zygotic transcription but is separable from the function of pioneer factors in restructuring chromatin accessibility.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 40441155
DOI 10.1016/j.molcel.2025.05.009
Crossref 10.1016/j.molcel.2025.05.009
mid: NIHMS2081331
pmc: PMC12181052
pii: S1097-2765(25)00414-9