Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains very limited. Here, we identified the native MORF complex as a histone H3K23-specific acetyltransferase and elucidated its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF subunits, H3K23ac, and H3K14ac at promoters of MORF target genes in vivo. Together, our findings reveal a high correlation between two acetylation sites, H3K23 and H3K14, and suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate gene transcription.