Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer
Menée à l'aide de lignées cellulaires, de modèles murins et de données génétiques et cliniques portant sur 12 personnes présentant une déficience intellectuelle syndromique, cette étude met en évidence, dans les cellules cancéreuses et chez les personnes présentant des troubles du développement neural, la présence de variants du gène BRPF1 responsables d'une déficience au niveau de la propionylation de l'histone H3
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.