KAT6B overexpression in mice causes aggression, anxiety, and epilepsy
Maria I. Bergamasco,
Ezgi Ozturk,
Pablo M. Casillas-Espinosa,
Alexandra L. Garnham,
Waruni Abeysekera,
Verena C. Wimmer,
Pradeep Rajasekhar,
Hannah K. Vanyai,
Lachlan Whitehead,
Marnie E. Blewitt,
Kelly Rogers,
Adam P. Vogel,
Anthony J. Hannan,
Gordon K. Smyth,
Nigel C. Jones,
Tim Thomas,
Anne K. Voss
Affiliations
Maria I. Bergamasco
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Ezgi Ozturk
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville VIC 3052, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Neurology, Alfred Hospital, Melbourne, Melbourne, VIC 3004, Australia
Pablo M. Casillas-Espinosa
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville VIC 3052, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Neurology, Alfred Hospital, Melbourne, Melbourne, VIC 3004, Australia
Alexandra L. Garnham
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Waruni Abeysekera
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Verena C. Wimmer
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Pradeep Rajasekhar
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Hannah K. Vanyai
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Lachlan Whitehead
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Marnie E. Blewitt
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Kelly Rogers
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
Adam P. Vogel
Centre for Neurosciences of Speech, The University of Melbourne, Melbourne, VIC 3052, Australia; Redenlab Inc, Melbourne, VIC 3000, Australia
Anthony J. Hannan
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC 3010, Australia
Gordon K. Smyth
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia
Nigel C. Jones
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville VIC 3052, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Neurology, Alfred Hospital, Melbourne, Melbourne, VIC 3004, Australia
Tim Thomas
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; Corresponding author
Anne K. Voss
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; Corresponding author
Summary: 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.
