Acetylation of histone lysine residues is catalysed by histone acetyltransferases and generally associated with gene expression. De novo, heterozygous mutations in the KAT6B gene, encoding the MYST family histone acetyltransferase KAT6B (MYST4/MORF/QKF), underlie two major intellectual disability disorders, Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GPS). KAT6B plays essential roles in the developing cortex, however, the mechanisms by which KAT6B impairment results in defective cortex development and intellectual disability remain unknown. Of the two syndromes caused by heterozygous mutations in KAT6B, GPS is more severe. To explain this difference, it has been hypothesised that GPS might result from an abnormal gain of KAT6B function, although this is yet to be experimentally examined.
We demonstrate here that overexpression of the Kat6b gene in the mouse model results in elevated aggression, anxiety and a predisposition to epileptic seizures. Mechanistically, we show that Kat6b overexpression promotes neural stem cell proliferation, neuronal differentiation and neurite outgrowth in vivo and in vitro. We show that Kat6b overexpression results in an increase in histone H3 lysine 9 acetylation and drives expression of neurogenesis-associated transcriptional regulators. Taken together, our results identify a potential histone lysine target of KAT6B, define its gene targets and specify its role as an essential facilitator of neural stem cell proliferation and neurogenesis.