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.
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.
Metrics
-
- 2,399
- views
-
- 391
- downloads
-
- 21
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability
eLife 12:e82596.
https://doi.org/10.7554/eLife.82596
Further reading
-
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
In the bacterium M. smegmatis, an enzyme called MftG allows the cofactor mycofactocin to transfer electrons released during ethanol metabolism to the electron transport chain.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, for example, reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.
