The BAF complex enhances transcription through interaction with H3K56ac in the histone globular domain

Histone post-translational modifications play pivotal roles in eukaryotic gene expression. To date, most studies have focused on modifications in unstructured histone N-terminal tail domains and their binding proteins. However, transcriptional regulation by chromatin-effector proteins that directly recognize modifications in histone globular domains has yet to be clearly demonstrated, despite the richness of their multiple modifications. Here, we show that the ATP-dependent chromatin-remodeling BAF complex stimulates p53-dependent transcription through direct interaction with H3K56ac located on the lateral surface of the histone globular domain. Mechanistically, the BAF complex recognizes nucleosomal H3K56ac via the DPF domain in the DPF2 subunit and exhibits enhanced nucleosome-remodeling activity in the presence of H3K56ac. We further demonstrate that a defect in H3K56ac–BAF complex interaction leads to impaired p53-dependent gene expression and DNA damage responses. Our study provides direct evidence that histone globular domain modifications participate in the regulation of gene expression. Overall design: The BAF complex harboring R350H mutation in the DPF2 subunit exhibited a defect in physical interaction with nucleosomal H3K56ac. To investigate the effect of DPF2-mediated interactions of the BAF complex with H3K56ac on gene expression in DNA-damaging conditions, we introduced the DPF2 R350H mutation into the genome of HCT116 cells using the CRISPR/Cas9 gene-editing system. We then performed RNA sequencing analyses on WT and DPF2 R350H HCT116 cells in the presence and absence of doxorubicin treatments.