Gene-specific mechanisms direct Glucocorticoid Receptor-driven repression of inflammatory response genes in macrophages

  1. Maria A Sacta
  2. Bowranigan Tharmalingam
  3. Maddalena Coppo
  4. David A Rollins
  5. Dinesh K Deochand
  6. Bradley Benjamin
  7. Li Yu
  8. Bin Zhang
  9. Xiaoyu Hu
  10. Rong Li
  11. Yurii Chinenov
  12. Inez Rogatsky  Is a corresponding author
  1. Hospital for Special Surgery, United States
  2. Hospital For Special Surgery, United States
  3. Tsinghua University, China
  4. The University of Texas Health Science Center at San Antonio, United States

Abstract

The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class, however, it effects repression by targeting distinct temporal events and components of transcriptional machinery.

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The following data sets were generated

Article and author information

Author details

  1. Maria A Sacta

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bowranigan Tharmalingam

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maddalena Coppo

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. David A Rollins

    Research Institute, Hospital For Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dinesh K Deochand

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Bradley Benjamin

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Li Yu

    Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Bin Zhang

    Institute for Immunology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6232-6768
  9. Xiaoyu Hu

    Research InstituteInstitute for Immunology, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rong Li

    Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6471-6580
  11. Yurii Chinenov

    Research Institute, Hospital for Special Surgery, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Inez Rogatsky

    Research Institute, Hospital for Special Surgery, New York, United States
    For correspondence
    rogatskyi@hss.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3514-5077

Funding

National Institutes of Health (R01DK099087)

  • Maria A Sacta
  • Bowranigan Tharmalingam
  • Maddalena Coppo
  • David A Rollins
  • Dinesh K Deochand
  • Bradley Benjamin
  • Yurii Chinenov
  • Inez Rogatsky

National Natural Science Foundation of China (91642115)

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

National Natural Science Foundation of China (8151101184)

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

U.S. Department of Defense (PR130049)

  • Bowranigan Tharmalingam
  • Maddalena Coppo
  • Yurii Chinenov
  • Inez Rogatsky

Rheumatology Research Foundation

  • David A Rollins
  • Yurii Chinenov
  • Inez Rogatsky

Hospital for Special Surgery David Rosensweig Genomic Center

  • Maddalena Coppo
  • Yurii Chinenov
  • Inez Rogatsky

Ministry of Science and Technology of the People's Republic of China

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

National Natural Science Foundation of China (81422019)

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

Tsinghua University

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

National Institutes of Health (R01 CA220578)

  • Rong Li

National Natural Science Foundation of China (81571580)

  • Li Yu
  • Bin Zhang
  • Xiaoyu Hu

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Mice were maintained in the Weill Cornell Animal Facility in compliance with guidelines from the Weill Cornell Animal Care and Use Committee (Protocol approval # 2015-0050).

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: January 7, 2018
  2. Accepted: January 28, 2018
  3. Accepted Manuscript published: February 9, 2018 (version 1)
  4. Version of Record published: February 21, 2018 (version 2)

Copyright

© 2018, Sacta 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. Maria A Sacta
  2. Bowranigan Tharmalingam
  3. Maddalena Coppo
  4. David A Rollins
  5. Dinesh K Deochand
  6. Bradley Benjamin
  7. Li Yu
  8. Bin Zhang
  9. Xiaoyu Hu
  10. Rong Li
  11. Yurii Chinenov
  12. Inez Rogatsky
(2018)
Gene-specific mechanisms direct Glucocorticoid Receptor-driven repression of inflammatory response genes in macrophages
eLife 7:e34864.
https://doi.org/10.7554/eLife.34864

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