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

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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 is challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms underlie 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 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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind55
Sider (fra-til)679-692
ISSN1061-4036
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank the members of the Choudhary laboratory for their helpful discussions. We thank E. Maskey for her excellent technical assistance. The Novo Nordisk Foundation Center for Protein Research is financially supported by the Novo Nordisk Foundation (no. NNF14CC0001). C.C. was supported by the Novo Nordisk Foundation (nos. NNF14OC0008541 and NNF22OC0074677). This work was funded by the European Commission FP7 grant (no. SyBoSS FP7-242129). Y.H. was supported by a Grant‐in‐Aid for JSPS Overseas Postdoctoral Fellows. S.K. was supported by a Lundbeck Foundation Fellowship (no. R347-2020-2170). We thank the SyBoSS partners K. Anastassiadis, F. Steward, A. Smith and W. Skarnes for sharing E14TG2a Oct4-IRES-Puro mouse ESCs. We thank Abcam, Cell Signaling Technology, Thermo Fisher Scientific, Active Motif and RevMAb Biosciences for providing some of the antibody samples for testing. We thank the CPR Imaging Platform, the CPR Big Data Management Platform and the CPR and DanStem Genomics Platform for their assistance. We thank the ENCODE Consortium and the ENCODE production laboratory for generating and sharing the data. We also thank Fulco et al. and Gasperini et al. for providing unrestricted access to their data.

Publisher Copyright:
© 2023, The Author(s).

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