KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain

Heterozygous mutations in the histone lysine acetyltransferase gene <i>KAT6B</i> (<i>MYST4/MORF/QKF</i>) underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular <i>Sox2</i>, which is a key driver of neural progenitor proliferation, multipotency and brain development. In the fetal cortex, KAT6B occupied the <i>Sox2</i> locus. Loss of KAT6B caused a reduction in <i>Sox2</i> promoter activity in NSPCs. <i>Sox2</i> overexpression partially rescued the proliferative defect of <i>Kat6b</i> ^-/- NSPCs. Collectively, these results elucidate molecular requirements for KAT6B in brain development and identify key KAT6B targets in neural precursor cells and the developing brain.