@article{bd0846439ee84e39a11a3d3f519d5832,
title = "Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer",
abstract = "Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.",
author = "Kezhi Yan and Justine Rousseau and Keren Machol and Cross, {Laura A.} and Agre, {Katherine E.} and Gibson, {Cynthia Forster} and Anne Goverde and Engleman, {Kendra L.} and Hannah Verdin and {de Baere}, Elfride and Lorraine Potocki and Dihong Zhou and Maxime Cadieux-Dion and Bellus, {Gary A.} and Wagner, {Monisa D.} and Hale, {Rebecca J.} and Natacha Esber and Riley, {Alan F.} and Solomon, {Benjamin D.} and Cho, {Megan T.} and Kirsty McWalter and Roy Eyal and Hainlen, {Meagan K.} and Mendelsohn, {Bryce A.} and Porter, {Hillary M.} and Lanpher, {Brendan C.} and Lewis, {Andrea M.} and Juliann Savatt and Isabelle Thiffault and Bert Callewaert and Campeau, {Philippe M.} and Yang, {Xiang Jiao}",
note = "Funding Information: This project was supported, in part, by operating grants from Canadian Institutes of Health Research (CIHR; to P.M.C. and X.-J.Y.), Natural Sciences and Engineering Research Council of Canada (NSERC; to X.-J.Y.), and Cancer Research Society (to X.-J.Y.). E.D.B. and B.C. are senior clinical investigators, and H.V. is a postdoctoral fellow of the Research Foundation–Flanders. Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",
year = "2020",
month = jan,
day = "22",
doi = "10.1126/sciadv.aax0021",
language = "English (US)",
volume = "6",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "4",
}