1. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer
- Author
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Benjamin D. Solomon, Cynthia Forster Gibson, Kezhi Yan, Juliann M. Savatt, Bert Callewaert, Justine Rousseau, Hannah Verdin, Bryce A. Mendelsohn, Roy Eyal, Kendra Engleman, Gary A. Bellus, Katherine Agre, Lorraine Potocki, Andrea M. Lewis, Keren Machol, Brendan C. Lanpher, Alan F. Riley, Rebecca J. Hale, Anne Goverde, Isabelle Thiffault, Natacha Esber, Xiang-Jiao Yang, Elfride De Baere, Philippe M. Campeau, Megan T. Cho, Hillary M. Porter, Kirsty McWalter, Laura A Cross, Monisa D. Wagner, Dihong Zhou, Meagan K. Hainlen, Maxime Cadieux-Dion, and Clinical Genetics
- Subjects
Lysine Acetyltransferases ,DNA Mutational Analysis ,Diseases and Disorders ,HBO1 ACETYLTRANSFERASE ,Histones ,Mice ,0302 clinical medicine ,Neoplasms ,Medicine and Health Sciences ,Research Articles ,Histone Acetyltransferases ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,SciAdv r-articles ,Brain ,Acetylation ,Syndrome ,Magnetic Resonance Imaging ,3. Good health ,Chromatin ,GENOME ,DNA-Binding Proteins ,Histone ,Phenotype ,lipids (amino acids, peptides, and proteins) ,Disease Susceptibility ,medicine.drug ,Research Article ,Protein Binding ,EXPRESSION ,ACETYLATION ,H3K14 ,KAT6B ,complex mixtures ,Models, Biological ,Cell Line ,03 medical and health sciences ,Histone H3 ,SDG 3 - Good Health and Well-being ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Vorinostat ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,MUTATIONS ,RECOGNITION ,GENE ,Molecular biology ,Bromodomain ,REGULATOR BRPF1 ,Neurodevelopmental Disorders ,Multiprotein Complexes ,Mutation ,biology.protein ,bacteria ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Two lysine acyltransferases govern histone H3 propionylation at lysine 23 in normal and pathological conditions., 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.
- Published
- 2020
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