Nucleosome conformation dictates the histone code
- EpiCypher, United States
- University of Colorado Anschutz Medical Campus, United States
- University of North Carolina at Chapel Hill, United States
Abstract
Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP : histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher order factors. Here we show that the [BPTF PHD finger and bromodomain : histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the 'histone code' concept and interrogate it at the nucleosome level.
Data availability
Raw data from dCypher assays is in Supplementary File 1. All sequencing data has been deposited in the NCBU Gene Expression Omnibus (GEO) with accession number GSE150617.
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Nucleosome conformation dictates the histone codeNCBI Gene Expression Omnibus, GSE150617.
Article and author information
Author details
Eileen T McAnarney
Krzysztof Krajewski
Catherine A Musselman
Funding
National Institutes of Health (2T32GM008365-26A1)
- Harrison A Fuchs
National Institutes of Health (P30CA086862)
- Catherine A Musselman
National Science Foundation (CAREER-1452411)
- Harrison A Fuchs
National Institutes of Health (R35GM128705)
- Harrison A Fuchs
- Catherine A Musselman
National Institutes of Health (R43CA236474)
- Matthew R Marunde
- Jonathan M Burg
- Irina K Popova
- Anup Vaidya
- Nathan W Hall
- Ellen N Weinzapfel
- Matthew J Meiners
- Rachel Watson
- Zachary B Gillespie
- Hailey F Taylor
- Laylo Mukhsinova
- Ugochi C Onuoha
- Sarah A Howard
- Katherine Novitzky
- Eileen T McAnarney
- Krzysztof Krajewski
- Martis W Cowles
- Marcus A Cheek
- Zu-Wen Sun
- Bryan J Venters
- Michael-C Keogh
National Institutes of Health (R44GM117683)
- Matthew R Marunde
- Jonathan M Burg
- Irina K Popova
- Anup Vaidya
- Nathan W Hall
- Ellen N Weinzapfel
- Matthew J Meiners
- Rachel Watson
- Zachary B Gillespie
- Hailey F Taylor
- Laylo Mukhsinova
- Ugochi C Onuoha
- Sarah A Howard
- Katherine Novitzky
- Eileen T McAnarney
- Krzysztof Krajewski
- Martis W Cowles
- Marcus A Cheek
- Zu-Wen Sun
- Bryan J Venters
- Michael-C Keogh
National Institutes of Health (R44CA214076)
- Matthew R Marunde
- Jonathan M Burg
- Irina K Popova
- Anup Vaidya
- Nathan W Hall
- Ellen N Weinzapfel
- Matthew J Meiners
- Rachel Watson
- Zachary B Gillespie
- Hailey F Taylor
- Laylo Mukhsinova
- Ugochi C Onuoha
- Sarah A Howard
- Katherine Novitzky
- Eileen T McAnarney
- Krzysztof Krajewski
- Martis W Cowles
- Marcus A Cheek
- Zu-Wen Sun
- Bryan J Venters
- Michael-C Keogh
National Institutes of Health (R44GM116584)
- Matthew R Marunde
- Jonathan M Burg
- Irina K Popova
- Anup Vaidya
- Nathan W Hall
- Ellen N Weinzapfel
- Matthew J Meiners
- Rachel Watson
- Zachary B Gillespie
- Hailey F Taylor
- Laylo Mukhsinova
- Ugochi C Onuoha
- Sarah A Howard
- Katherine Novitzky
- Eileen T McAnarney
- Krzysztof Krajewski
- Martis W Cowles
- Marcus A Cheek
- Zu-Wen Sun
- Bryan J Venters
- Michael-C Keogh
National Institutes of Health (R44DE029633)
- Matthew R Marunde
- Jonathan M Burg
- Irina K Popova
- Anup Vaidya
- Nathan W Hall
- Ellen N Weinzapfel
- Matthew J Meiners
- Rachel Watson
- Zachary B Gillespie
- Hailey F Taylor
- Laylo Mukhsinova
- Ugochi C Onuoha
- Sarah A Howard
- Katherine Novitzky
- Eileen T McAnarney
- Krzysztof Krajewski
- Martis W Cowles
- Marcus A Cheek
- Zu-Wen Sun
- Bryan J Venters
- 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
© 2024, Marunde 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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Nucleosome conformation dictates the histone code
eLife 13:e78866.
https://doi.org/10.7554/eLife.78866
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During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.
