1. Biochemistry and Chemical Biology
  2. Chromosomes and Gene Expression

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability

  1. Kanishk Jain
  2. Matthew R Marunde
  3. Jonathan M Burg
  4. Susan L Gloor
  5. Faith M Joseph
  6. Karl F Poncha
  7. Zachary B Gillespie
  8. Keli L Rodriguez
  9. Irina K Popova
  10. Nathan W Hall
  11. Anup Vaidya
  12. Sarah A Howard
  13. Hailey F Taylor
  14. Laylo Mukhsinova
  15. Ugochi C Onuoha
  16. Emily F Patteson
  17. Spencer W Cooke
  18. Bethany C Taylor
  19. Ellen N Weinzapfel
  20. Marcus A Cheek
  21. Matthew J Meiners
  22. Geoffrey C Fox
  23. Kevin EW Namitz
  24. Martis W Cowles
  25. Krzysztof Krajewski
  26. Zu-Wen Sun
  27. Michael S Cosgrove
  28. Nicolas Young
  29. Michael-C Keogh  Is a corresponding author
  30. Brian D Strahl  Is a corresponding author
  1. University of North Carolina at Chapel Hill, United States
  2. EpiCypher, United States
  3. Baylor College of Medicine, United States
  4. Pennsylvania State University, United States
  5. SUNY Upstate Medical University, United States
https://doi.org/10.7554/eLife.82596
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Cite this article
  1. Kanishk Jain
  2. Matthew R Marunde
  3. Jonathan M Burg
  4. Susan L Gloor
  5. Faith M Joseph
  6. Karl F Poncha
  7. Zachary B Gillespie
  8. Keli L Rodriguez
  9. Irina K Popova
  10. Nathan W Hall
  11. Anup Vaidya
  12. Sarah A Howard
  13. Hailey F Taylor
  14. Laylo Mukhsinova
  15. Ugochi C Onuoha
  16. Emily F Patteson
  17. Spencer W Cooke
  18. Bethany C Taylor
  19. Ellen N Weinzapfel
  20. Marcus A Cheek
  21. Matthew J Meiners
  22. Geoffrey C Fox
  23. Kevin EW Namitz
  24. Martis W Cowles
  25. Krzysztof Krajewski
  26. Zu-Wen Sun
  27. Michael S Cosgrove
  28. Nicolas Young
  29. Michael-C Keogh
  30. Brian D Strahl
(2023)
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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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.

The following data sets were generated

Article and author information

Author details

  1. Kanishk Jain

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.

  2. Matthew R Marunde

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

  3. Jonathan M Burg

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

  4. Susan L Gloor

    EpiCypher, Durham, United States
    Competing interests
    Susan L Gloor, is affiliated with EpiCypher, Inc. The author has no financial interests to declare..

  5. Faith M Joseph

    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  6. Karl F Poncha

    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  7. Zachary B Gillespie

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

  8. Keli L Rodriguez

    EpiCypher, Durham, United States
    Competing interests
    Keli L Rodriguez, is affiliated with EpiCypher, Inc. The author has no financial interests to declare..

  9. Irina K Popova

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

  10. Nathan W Hall

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

  11. Anup Vaidya

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

  12. Sarah A Howard

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

  13. Hailey F Taylor

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

  14. Laylo Mukhsinova

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

  15. Ugochi C Onuoha

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

  16. Emily F Patteson

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

  17. Spencer W Cooke

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.

  18. Bethany C Taylor

    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  19. Ellen N Weinzapfel

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

  20. Marcus A Cheek

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

  21. Matthew J Meiners

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

  22. Geoffrey C Fox

    Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5898-0847

  23. Kevin EW Namitz

    Pennsylvania State University, State College, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4434-1475

  24. Martis W Cowles

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

  25. Krzysztof Krajewski

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Krzysztof Krajewski, owns options in EpiCypher, Inc..

  26. Zu-Wen Sun

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

  27. Michael S Cosgrove

    Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States
    Competing interests
    Michael S Cosgrove, owns stock/serves on the Consultant Advisory Board for Kathera Bioscience Inc. and holds266 US patents (8,133,690; 8,715,678; and 10,392,423) for compounds/methods for inhibiting267 SET1/MLL family complexes.

  28. Nicolas Young

    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3323-2815

  29. Michael-C Keogh

    EpiCypher, Durham, United States
    For correspondence
    mkeogh@epicypher.com
    Competing interests
    Michael-C Keogh, is a BOD member of EpiCypher Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2219-8623

  30. Brian D Strahl

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    brian_strahl@med.unc.edu
    Competing interests
    Brian D Strahl, is a co-founder and BOD member of EpiCypher, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4947-6259

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.

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  1. Kanishk Jain
  2. Matthew R Marunde
  3. Jonathan M Burg
  4. Susan L Gloor
  5. Faith M Joseph
  6. Karl F Poncha
  7. Zachary B Gillespie
  8. Keli L Rodriguez
  9. Irina K Popova
  10. Nathan W Hall
  11. Anup Vaidya
  12. Sarah A Howard
  13. Hailey F Taylor
  14. Laylo Mukhsinova
  15. Ugochi C Onuoha
  16. Emily F Patteson
  17. Spencer W Cooke
  18. Bethany C Taylor
  19. Ellen N Weinzapfel
  20. Marcus A Cheek
  21. Matthew J Meiners
  22. Geoffrey C Fox
  23. Kevin EW Namitz
  24. Martis W Cowles
  25. Krzysztof Krajewski
  26. Zu-Wen Sun
  27. Michael S Cosgrove
  28. Nicolas Young
  29. Michael-C Keogh
  30. Brian D Strahl
(2023)
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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https://doi.org/10.7554/eLife.82596

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