Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
Sci Adv
; 6(4): eaax0021, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-32010779
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Histonas
/
Proteínas Adaptadoras de Transdução de Sinal
/
Proteínas de Ligação a DNA
/
Histona Acetiltransferases
/
Transtornos do Neurodesenvolvimento
/
Neoplasias
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article