biostudies-literatureUnknown28(3)Bergamasco MIAustralian Government Department of DefenceThe Chan Zuckerberg InitiativeNational Health and Medical Research CouncilAustralian Government Department of Health and Aged CareLorenzo and Pamela Galli Charitable TrustLoss of the gene encoding the histone acetyltransferase KAT6B (MYST4/MORF/QKF) causes developmental brain abnormalities as well as behavioral and cognitive defects in mice. In humans, heterozygous variants in the KAT6B gene cause two cognitive disorders, Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM:603736) and genitopatellar syndrome (GTPTS; OMIM:606170). Although the effects of KAT6B homozygous and heterozygous mutations have been documented in humans and mice, KAT6B gain-of-function effects have not been reported. Here, we show that overexpression of the Kat6b gene in mice caused aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression led to an increase in histone H3 lysine 9 acetylation and upregulation of genes driving nervous system development and neuronal differentiation. Kat6b overexpression additionally promoted neural stem cell proliferation and favored neuronal over astrocyte differentiation in vivo and in vitro. Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development.iScience111953https://www.ebi.ac.uk/biostudies/studies/S-EPMC11904597biostudies-literatureKAT6B overexpression in mice causes aggression, anxiety, and epilepsy.PMC11904597Smyth GKBlewitt MEWimmer VCVogel APOzturk EWhitehead LBergamasco MIGarnham ALAbeysekera WRajasekhar PThomas TVoss AKVanyai HKRogers KJones NCHannan AJCasillas-Espinosa PMfalseKAT6B overexpression in mice causes aggression, anxiety, and epilepsy.Loss of the gene encoding the histone acetyltransferase KAT6B (MYST4/MORF/QKF) causes developmental brain abnormalities as well as behavioral and cognitive defects in mice. In humans, heterozygous variants in the KAT6B gene cause two cognitive disorders, Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM:603736) and genitopatellar syndrome (GTPTS; OMIM:606170). Although the effects of KAT6B homozygous and heterozygous mutations have been documented in humans and mice, KAT6B gain-of-function effects have not been reported. Here, we show that overexpression of the Kat6b gene in mice caused aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression led to an increase in histone H3 lysine 9 acetylation and upregulation of genes driving nervous system development and neuronal differentiation. Kat6b overexpression additionally promoted neural stem cell proliferation and favored neuronal over astrocyte differentiation in vivo and in vitro. Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development.2025-01-01T00:00:00Z2025 Mar2026-06-02T21:11:24.914Z2025-04-04T03:01:33.428ZS-EPMC119045974008371610.1016/j.isci.2025.111953