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

Research output: Contribution to journalArticlepeer-review

26 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
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by research grants from the Natural Sciences and Engineering Research Council of Canada (to XJY), Canadian Institutes of Health Research (CIHR, to XJY and PMC), Cancer Research Society (to XJY), and National Institutes of Health (CA129537 and GM109768, to TKP). This study makes use of DECIPHER (, which is funded by Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003); see ref. 78 or html for full acknowledgment. LL received stipend support from China Scholarship Council, the Clifford C.F. Wong Fellowship program, a CIHR/FRSQ training grant in cancer research for the McGill Integrated Cancer Research Training Program, and the Canderel Foundation.

Publisher Copyright:
© 2020, American Society for Clinical Investigation.


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