Acetylation of histone H2B marks active enhancers and predicts CBP/p300 target genes

Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength, and identifying their target genes remains challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a genuine signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms afford the distinct H2BNTac specificity. (1) Unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300. (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays, and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms the current state-of-the-art models in predicting CBP/p300 target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling CBP/p300-dependent gene regulation. H2BNTac ChIP-seq before and after A-485 treatment in mES cell grown in 2i. As a reference, H3K9ac, H3K4me3, H3K27ac, H3K27me3, Med1 ChIP-seq are included. H2BK20ac and H3K27ac ChIP-seq in K562 cell are included. H3K27ac and H2BK20ac ChIP seq were performed in mouse ESC and human K562 cell lines.