Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

Lin Li, Mohammad Ghorbani, Monika Weisz-Hubshman, Justine Rousseau, Isabelle Thiffault, Rhonda E. Schnur, Catherine Breen, Renske Oegema, Marjan M.M. Weiss, Quinten Waisfisz, Sara Welner, Helen Kingston, Jordan A. Hills, Elles M.J. Boon, Lina Basel-Salmon, Osnat Konen, Hadassa Goldberg-Stern, Lily Bazak, Shay Tzur, Jianliang JinXiuli Bi, Michael Bruccoleri, Kirsty McWalter, Megan T. Cho, Maria Scarano, G. Bradley Schaefer, Susan S. Brooks, Susan Starling Hughes, K. L.I. Van Gassen, Johanna M. Van Hagen, Tej K. Pandita, Pankaj B. Agrawal, Philippe M. Campeau*, Xiang Jiao Yang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

Original languageEnglish
Pages (from-to)1431-1445
Number of pages15
JournalJournal of Clinical Investigation
Issue number3
StatePublished - 2 Mar 2020


FundersFunder number
Canderel Foundation
Health Innovation Challenge FundHICF-1009-003
National Institutes of HealthCA129537
National Institutes of Health
National Institute of General Medical SciencesR01GM109768
National Institute of General Medical Sciences
Cancer Research Society
Wellcome Trust
Canadian Institutes of Health Research
Natural Sciences and Engineering Research Council of Canada
China Scholarship Council


    Dive into the research topics of 'Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability'. Together they form a unique fingerprint.

    Cite this