Effects of loss of KAT6A on histone acetylation and methylation levels, as well as MLL1 and POLR2A occupancy

Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, an intellectual disability syndrome. The profound effects of pathogenic variants in only one allele of KAT6A on cognitive development and functions raises the question what effects heterozygous and homozygous loss of KAT6A may have on gene expression and chromatin modifications, specifically in a neural cell type that is functionally affected by loss of KAT6A. To address this question, we established that murine neural stem and progenitor cells form fewer neurons after loss of one and two alleles of Kat6a and used these cells to conduct automated chromatin profiling. We determined within the same cell preparation acetylation at histone H3 lysines 9, 14 and 23, RNA polymerase II (POLR2A) and MLL1 occupancy, as well as levels of methylation at histone H3 lysine 4 (H3K4), the MLL1 target, and compared these chromatin profiling results to the effects of loss of KAT6A on gene expression.