PRJNA517640
A mammalian DNA Repair complex licenses acetylation of histone variant H2A.Z by KAT2A at active promoters during transcription
Post-translational modifications of the histone variant H2A.Z accompany gene transactivation but the H2A.Z modifying enzymes in mammals remain largely elusive. Here chemical inhibition and genome-wide analysis reveal the hitherto unknown function of the mammalian KAT2A (GCN5) as the histone acetyl transferase (HAT) of H2A.Z at the promoters of a subset of transactivated genes. Intriguingly, expression of these genes also depends on the trimeric nucleotide excision repair XPC- RAD23-CEN2 complex. We established that this complex interacts both with H2A.Z and KAT2A to drive the recruitment of the HAT at transactivated promoters and license H2A.Z acetylation. Functionally, we further determined that KAT2A and the KAT2A-containing ATAC HAT module acetylate in vitro H2A.Z, but not H2A, on several defined lysine residues. Using a nonacetylable H2A.Z mutant and several inhibitors of the BET family of bromodomain proteins we finally reveal that H2A.Zac recruits the epigenetic reader and transcription co-regulator BRD2, essential to pre- initiation complex formation. Our study implicate KAT2A as a H2A.Z HAT in mammals and the XPC- RAD23-CEN2 complex as a molecular bridge between histone variants and transcription co- activators, licensing the reshaping of the promoter epigenetic landscape during transcription.