An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability
- University of North Carolina at Chapel Hill, United States
- EpiCypher, United States
- Baylor College of Medicine, United States
- Pennsylvania State University, United States
- SUNY Upstate Medical University, United States
Abstract
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g., K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has broader extension. Here we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation 'chromatin switch' on the H3 tail that modulates read-write accessibility in nucleosomes and resolve the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.
Data availability
Raw MS data is publicly available and has been uploaded to the UCSD MassIVE database (ftp://massive.ucsd.edu/MSV000089089/ and ftp://massive.ucsd.edu/MSV000091578/). All analyzed data are reported in the manuscript and Supporting Files.
Article and author information
Author details
Funding
American Cancer Society (PF-20-149-01-DMC)
- Kanishk Jain
National Cancer Institute (R44CA214076)
- Michael-C Keogh
National Institute of General Medical Sciences (R44GM116584)
- Michael-C Keogh
National Institute of General Medical Sciences (R35GM126900)
- Brian D Strahl
National Institute of General Medical Sciences (R01GM139295)
- Nicolas Young
National Cancer Institute (T32CA217824)
- Kanishk Jain
National Institute of General Medical Sciences (P01AG066606)
- Nicolas Young
National Cancer Institute (R01CA193235)
- Nicolas Young
National Cancer Institute (R01CA140522)
- Michael S Cosgrove
National Cancer Institute (R43CA236474)
- Michael-C Keogh
National Institute of General Medical Sciences (R44GM117683)
- Michael-C Keogh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Xiaobing Shi, Van Andel Institute, United States
Version history
- Preprint posted: February 28, 2022 (view preprint)
- Received: August 10, 2022
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
- Version of Record published: May 30, 2023 (version 2)
Copyright
© 2023, Jain et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability
eLife 12:e82596.
https://doi.org/10.7554/eLife.82596
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