JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes

  1. Schuyler Lee
  2. Haolin Liu
  3. Ryan Hill
  4. Chunjing Chen
  5. Xia Hong
  6. Fran Crawford
  7. Molly Kingsley
  8. Qianqian Zhang
  9. Xinjian Liu
  10. Zhongzhou Chen
  11. Andreas Lengeling
  12. Kathrin Maria Bernt
  13. Philippa Marrack
  14. John Kappler
  15. Qiang Zhou
  16. Chuan-Yuan Li
  17. Yuhua Xue
  18. Kirk Hansen
  19. Gongyi Zhang  Is a corresponding author
  1. National Jewish Health, United States
  2. School of Medicine, Univeristy of Colorado at Anschutz Medical Center, United States
  3. Xiamen Univeristy, China
  4. Children Hospital, United States
  5. China Agriculture University, China
  6. Duke University Medical Center, United States
  7. Max-Planck-Society, Germany
  8. School of Medicine, University of Pennsylvannia, United States
  9. Howard Hughes Medical Institute, National Jewish Health, United States
  10. University of California, Berkeley, United States
  11. Xiamen University, China
  12. School of Medicine, University of Colorado at Anschutz Medical Center, United States

Abstract

More than 30% of genes in higher eukaryotes are regulated by promoter-proximal pausing of RNA polymerase II (Pol II). Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. The exact mechanism on how the sequestered P-TEFb is released from the 7SK snRNP complex and recruited to Pol II CTD remains unknown. In this report, we utilize mouse and human models to reveal methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, as the cognate substrate for Jumonji domain-containing 6 (JMJD6)’s novel proteolytic function. Our evidences consist of a crystal structure of JMJD6 bound to methyl-arginine, enzymatic assays of JMJD6 cleaving MePCE in vivo and in vitro, binding assays, and downstream effects of Jmjd6 knockout and overexpression on Pol II CTD phosphorylation. We propose that JMJD6 assists bromodomain containing 4 (BRD4) to recruit P-TEFb to Pol II CTD by disrupting the 7SK snRNP complex.

Data availability

Diffraction data have been deposited in PDB under the accession code 6mev,All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Schuyler Lee

    Biomedical Research, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  2. Haolin Liu

    Biomedical Research, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  3. Ryan Hill

    Genetics and Biochemistry, School of Medicine, Univeristy of Colorado at Anschutz Medical Center, Aurora, United States
    Competing interests
    No competing interests declared.
  4. Chunjing Chen

    School of Pharmaceutical Sciences, Xiamen Univeristy, Xiamen, China
    Competing interests
    No competing interests declared.
  5. Xia Hong

    Biomedical Research, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  6. Fran Crawford

    Biomedical Research, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  7. Molly Kingsley

    Pediatrics, Children Hospital, Aurora, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5921-3743
  8. Qianqian Zhang

    State Key Laboratory of Agrobiotechnology, China Agriculture University, Beijing, China
    Competing interests
    No competing interests declared.
  9. Xinjian Liu

    Department of Dermatology, Duke University Medical Center, Durham, United States
    Competing interests
    No competing interests declared.
  10. Zhongzhou Chen

    State Key Laboratroy of Agrobiotechnology, China Agriculture University, Beijing, China
    Competing interests
    No competing interests declared.
  11. Andreas Lengeling

    Adminstrative Headquaters, Max-Planck-Society, Munich, Germany
    Competing interests
    No competing interests declared.
  12. Kathrin Maria Bernt

    Pediatrics, School of Medicine, University of Pennsylvannia, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0691-356X
  13. Philippa Marrack

    Howard Hughes Medical Institute, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1883-3687
  14. John Kappler

    Howard Hughes Medical Institute, National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  15. Qiang Zhou

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7202-3947
  16. Chuan-Yuan Li

    Department of Dermatology, Duke University Medical Center, Durham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0418-6231
  17. Yuhua Xue

    Innovation Center of Cell Signaling Network, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
    Competing interests
    No competing interests declared.
  18. Kirk Hansen

    Genetics and Biochemistry, School of Medicine, University of Colorado at Anschutz Medical Center, Aurora, United States
    Competing interests
    No competing interests declared.
  19. Gongyi Zhang

    Biomedical Research, National Jewish Health, Denver, United States
    For correspondence
    zhangg@njhealth.org
    Competing interests
    Gongyi Zhang, has shares in NB Life Laboratory LLC, Colorado.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3010-3804

Funding

National Cancer Institute (CA201230)

  • Kathrin Maria Bernt

National Institute of Allergy and Infectious Diseases (AI007405)

  • Schuyler Lee

National Institute of Allergy and Infectious Diseases (AI074491)

  • Haolin Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Zhiguo Zhang, Columbia University, United States

Version history

  1. Received: November 25, 2019
  2. Accepted: February 11, 2020
  3. Accepted Manuscript published: February 12, 2020 (version 1)
  4. Version of Record published: March 10, 2020 (version 2)

Copyright

© 2020, Lee 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. Schuyler Lee
  2. Haolin Liu
  3. Ryan Hill
  4. Chunjing Chen
  5. Xia Hong
  6. Fran Crawford
  7. Molly Kingsley
  8. Qianqian Zhang
  9. Xinjian Liu
  10. Zhongzhou Chen
  11. Andreas Lengeling
  12. Kathrin Maria Bernt
  13. Philippa Marrack
  14. John Kappler
  15. Qiang Zhou
  16. Chuan-Yuan Li
  17. Yuhua Xue
  18. Kirk Hansen
  19. Gongyi Zhang
(2020)
JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes
eLife 9:e53930.
https://doi.org/10.7554/eLife.53930

Share this article

https://doi.org/10.7554/eLife.53930

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