1. Chromosomes and Gene Expression
  2. Structural Biology and Molecular Biophysics

Nucleosome conformation dictates the histone code

  1. Matthew R Marunde
  2. Harrison A Fuchs
  3. Jonathan M Burg
  4. Irina K Popova
  5. Anup Vaidya
  6. Nathan W Hall
  7. Ellen N Weinzapfel
  8. Matthew J Meiners
  9. Rachel Watson
  10. Zachary B Gillespie
  11. Hailey F Taylor
  12. Laylo Mukhsinova
  13. Ugochi C Onuoha
  14. Sarah A Howard
  15. Katherine Novitzky
  16. Eileen T McAnarney
  17. Krzysztof Krajewski
  18. Martis W Cowles
  19. Marcus A Cheek
  20. Zu-Wen Sun
  21. Bryan J Venters
  22. Michael-C Keogh  Is a corresponding author
  23. Catherine A Musselman  Is a corresponding author
  1. EpiCypher, United States
  2. University of Colorado Anschutz Medical Campus, United States
  3. University of North Carolina at Chapel Hill, United States
https://doi.org/10.7554/eLife.78866
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Cite this article
  1. Matthew R Marunde
  2. Harrison A Fuchs
  3. Jonathan M Burg
  4. Irina K Popova
  5. Anup Vaidya
  6. Nathan W Hall
  7. Ellen N Weinzapfel
  8. Matthew J Meiners
  9. Rachel Watson
  10. Zachary B Gillespie
  11. Hailey F Taylor
  12. Laylo Mukhsinova
  13. Ugochi C Onuoha
  14. Sarah A Howard
  15. Katherine Novitzky
  16. Eileen T McAnarney
  17. Krzysztof Krajewski
  18. Martis W Cowles
  19. Marcus A Cheek
  20. Zu-Wen Sun
  21. Bryan J Venters
  22. Michael-C Keogh
  23. Catherine A Musselman
(2024)
Nucleosome conformation dictates the histone code
eLife 13:e78866.
https://doi.org/10.7554/eLife.78866
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  3. Download .RIS

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.

The following data sets were generated

Article and author information

Author details

  1. Matthew R Marunde

    EpiCypher, Durham, United States
    Competing interests
    Matthew R Marunde, MRM is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  2. Harrison A Fuchs

    Department of Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    No competing interests declared.

  3. Jonathan M Burg

    EpiCypher, Durham, United States
    Competing interests
    Jonathan M Burg, JB is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  4. Irina K Popova

    EpiCypher, Durham, United States
    Competing interests
    Irina K Popova, IKP is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  5. Anup Vaidya

    EpiCypher, Durham, United States
    Competing interests
    Anup Vaidya, AV is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  6. Nathan W Hall

    EpiCypher, Durham, United States
    Competing interests
    Nathan W Hall, NWH is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  7. Ellen N Weinzapfel

    EpiCypher, Durham, United States
    Competing interests
    Ellen N Weinzapfel, ENW is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  8. Matthew J Meiners

    EpiCypher, Durham, United States
    Competing interests
    Matthew J Meiners, MJM is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  9. Rachel Watson

    EpiCypher, Durham, United States
    Competing interests
    Rachel Watson, RW is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  10. Zachary B Gillespie

    EpiCypher, Durham, United States
    Competing interests
    Zachary B Gillespie, ZBG is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  11. Hailey F Taylor

    EpiCypher, Durham, United States
    Competing interests
    Hailey F Taylor, HFT is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  12. Laylo Mukhsinova

    EpiCypher, Durham, United States
    Competing interests
    Laylo Mukhsinova, LM is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  13. Ugochi C Onuoha

    EpiCypher, Durham, United States
    Competing interests
    Ugochi C Onuoha, UCO is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  14. Sarah A Howard

    EpiCypher, Durham, United States
    Competing interests
    Sarah A Howard, SAH is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  15. Katherine Novitzky

    EpiCypher, Durham, United States
    Competing interests
    Katherine Novitzky, KN is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  16. Eileen T McAnarney

    EpiCypher, Durham, United States
    Competing interests
    Eileen T McAnarney, ETM is affiliated with EpiCypher Inc. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2337-2889

  17. Krzysztof Krajewski

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Krzysztof Krajewski, KK is affiliated with EpiCypher Inc. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7159-617X

  18. Martis W Cowles

    EpiCypher, Durham, United States
    Competing interests
    Martis W Cowles, MWC is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  19. Marcus A Cheek

    EpiCypher, Durham, United States
    Competing interests
    Marcus A Cheek, MAC is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  20. Zu-Wen Sun

    EpiCypher, Durham, United States
    Competing interests
    Zu-Wen Sun, ZS is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  21. Bryan J Venters

    EpiCypher, Durham, United States
    Competing interests
    Bryan J Venters, BJV is affiliated with EpiCypher Inc. The author has no financial interests to declare..

  22. Michael-C Keogh

    EpiCypher, Durham, United States
    For correspondence
    mkeogh@epicypher.com
    Competing interests
    Michael-C Keogh, MCK is a board member of EpiCypher Inc. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2219-8623

  23. Catherine A Musselman

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    For correspondence
    catherine.musselman@cuanschutz.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8356-7971

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.

Reviewing Editor

  1. Geeta J Narlikar, University of California, San Francisco, United States

Version history

  1. Preprint posted: February 22, 2022 (view preprint)
  2. Received: March 22, 2022
  3. Accepted: February 5, 2024
  4. Accepted Manuscript published: February 6, 2024 (version 1)
  5. Version of Record published: February 19, 2024 (version 2)

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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  1. Matthew R Marunde
  2. Harrison A Fuchs
  3. Jonathan M Burg
  4. Irina K Popova
  5. Anup Vaidya
  6. Nathan W Hall
  7. Ellen N Weinzapfel
  8. Matthew J Meiners
  9. Rachel Watson
  10. Zachary B Gillespie
  11. Hailey F Taylor
  12. Laylo Mukhsinova
  13. Ugochi C Onuoha
  14. Sarah A Howard
  15. Katherine Novitzky
  16. Eileen T McAnarney
  17. Krzysztof Krajewski
  18. Martis W Cowles
  19. Marcus A Cheek
  20. Zu-Wen Sun
  21. Bryan J Venters
  22. Michael-C Keogh
  23. Catherine A Musselman
(2024)
Nucleosome conformation dictates the histone code
eLife 13:e78866.
https://doi.org/10.7554/eLife.78866

Share this article

https://doi.org/10.7554/eLife.78866

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