Trrap-Dependent Histone Acetylation Specifically Regulates Cell-Cycle Gene Transcription to Control Neural Progenitor Fate Decisions

Fate decisions in neural progenitor cells are orchestrated via multiple pathways, and the role of histone acetylation in these decisions has been ascribed to a general function promoting gene activation. Here, we show that the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (Trrap) specifically regulates activation of cell-cycle genes, thereby integrating discrete cell-intrinsic programs of cell-cycle progression and epigenetic regulation of gene transcription in order to control neurogenesis. Deletion of Trrap impairs recruitment of HATs and transcriptional machinery specifically to E2F cell-cycle target genes, disrupting their transcription with consequent cell-cycle lengthening specifically within cortical apical neural progenitors (APs). Consistently, Trrap conditional mutants exhibit microcephaly because of premature differentiation of APs into intermediate basal progenitors and neurons, and overexpressing cell-cycle regulators in vivo can rescue these premature differentiation defects. These results demonstrate an essential and highly specific role for Trrap-mediated histone regulation in controlling cell-cycle progression and neurogenesis. [Display omitted] •The histone acetyltransferase cofactor Trrap is required for brain development•Deletion of Trrap leads to premature differentiation of neural progenitors•Trrap deletion specifically downregulates E2F-dependent cell-cycle genes•Specific histone acetylation activity balances neural progenitor fate decisions Brain-specific deletion of the histone acetyltransferase cofactor Trrap causes microencephaly because of cell-cycle lengthening and premature differentiation of neural progenitors, resulting from specific defects in E2F-dependent cell-cycle gene expression.