Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [CUT&Run]

Precise regulation of epigenetic marks is critical for proper lineage commitment throughout neurodevelopment. Mutations in members of the MSL acetyltransferase complex (MSLc), specific for H4K16ac, are associated with neurodevelopmental disorders in humans. However, the precise gene targets and enzymatic contributions of the MSLc during neural differentiation remain unclear. Through single-cell multi-omics analysis, we demonstrate that Msl1 deletion leads to severe neurodevelopmental defects, culminating in embryonic lethality by E10.5. Using a rapid depletion system, we uncoupled acute transcriptional effects from epigenetic memory and found that MSLc-mediated gene priming is responsible for faithful upregulation of crucial neurodevelopmental gene programs. The priming of the MSLc target genes is limited to the initial stages of differentiation following neuronal induction, where the MSLc facilitates chromatin accessibility at regulatory regions to, allowing for selective enhancer-promoter interactions and subsequent gene activation. Our study identifies the MSLc as a crucial epigenetic regulator during neurodevelopment, providing molecular insights into MSLc-associated developmental disorders.