Document Type

Article

Publication Date

1-22-2020

Identifier

DOI: 10.1126/sciadv.aax0021; PMCID: PMC6976298

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.

Journal Title

Sci Adv

Volume

6

Issue

4

First Page

0021

Last Page

0021

MeSH Keywords

Acetylation; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Brain; Cell Line; DNA Mutational Analysis; DNA-Binding Proteins; Disease Susceptibility; Genetic Predisposition to Disease; Histone Acetyltransferases; Histones; Humans; Magnetic Resonance Imaging; Mice; Mice, Knockout; Models, Biological; Multiprotein Complexes; Mutation; Neoplasms; Neurodevelopmental Disorders; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Syndrome

Keywords

Acetylation; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Brain; Cell Line; DNA Mutational Analysis; DNA-Binding Proteins; Disease Susceptibility; Genetic Predisposition to Disease; Histone Acetyltransferases; Histones; Humans; Magnetic Resonance Imaging; Mice; Mice, Knockout; Models, Biological; Multiprotein Complexes; Mutation; Neoplasms; Neurodevelopmental Disorders; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Syndrome

Comments

Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Publisher's Link: https://doi.org/10.1126/sciadv.aax0021

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