Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis

View ORCID ProfileMichelle Hoffner O’Connor, View ORCID ProfileAna Berglind, View ORCID ProfileMeaghan M. Kennedy, View ORCID ProfileBenjamin P. Keith, Zachary J. Lynch, View ORCID ProfileMatthew R. Schaner, View ORCID ProfileErin C. Steinbach, Jeremy Herzog, Omar K. Trad, View ORCID ProfileWilliam R. Jeck, View ORCID ProfileJanelle C. Arthur, View ORCID ProfileR. Balfour Sartor, View ORCID ProfileTerrence S. Furey, View ORCID ProfileShehzad Z. Sheikh
doi: https://doi.org/10.1101/2021.07.15.452570
Michelle Hoffner O’Connor
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
2Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michelle Hoffner O’Connor
Ana Berglind
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
2Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ana Berglind
Meaghan M. Kennedy
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Meaghan M. Kennedy
Benjamin P. Keith
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Benjamin P. Keith
Zachary J. Lynch
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew R. Schaner
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew R. Schaner
Erin C. Steinbach
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
4Department of Pediatrics, Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Erin C. Steinbach
Jeremy Herzog
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Omar K. Trad
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William R. Jeck
5Department of Pathology, Duke University, Durham, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for William R. Jeck
Janelle C. Arthur
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
6Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
7Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Janelle C. Arthur
R. Balfour Sartor
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for R. Balfour Sartor
Terrence S. Furey
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
8Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Terrence S. Furey
  • For correspondence: tsfurey@email.unc.edu sheisx@med.unc.edu
Shehzad Z. Sheikh
1Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
2Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Shehzad Z. Sheikh
  • For correspondence: tsfurey@email.unc.edu sheisx@med.unc.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Introduction In colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice.

Methods We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization.

Results Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice.

Conclusion We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.

Funding This work was funded in part through Helmsley Charitable Trust (SHARE Project 2), NIDDK P01DK094779, NIDDK 1R01DK104828, NIDDK P30-DK034987, NIDDK 1R01DK124617, NIH Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship (1F31DK122704), NIH T32 Genetics NIGMS Training Grant (T32-GM007092-43), NIH T32 Translational Medicine Training Grant (T32-GM122741), NIH T32 Gastroenterology Research Training Grant (T32-DK007737), and Crohn’s and Colitis Foundation Student Research Fellowship Award, and Gnotobiotic Animal Facility.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Disclosures: The authors have declared that no conflict of interest exists.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted July 16, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis
Michelle Hoffner O’Connor, Ana Berglind, Meaghan M. Kennedy, Benjamin P. Keith, Zachary J. Lynch, Matthew R. Schaner, Erin C. Steinbach, Jeremy Herzog, Omar K. Trad, William R. Jeck, Janelle C. Arthur, R. Balfour Sartor, Terrence S. Furey, Shehzad Z. Sheikh
bioRxiv 2021.07.15.452570; doi: https://doi.org/10.1101/2021.07.15.452570
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis
Michelle Hoffner O’Connor, Ana Berglind, Meaghan M. Kennedy, Benjamin P. Keith, Zachary J. Lynch, Matthew R. Schaner, Erin C. Steinbach, Jeremy Herzog, Omar K. Trad, William R. Jeck, Janelle C. Arthur, R. Balfour Sartor, Terrence S. Furey, Shehzad Z. Sheikh
bioRxiv 2021.07.15.452570; doi: https://doi.org/10.1101/2021.07.15.452570

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Immunology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3689)
  • Biochemistry (7789)
  • Bioengineering (5674)
  • Bioinformatics (21282)
  • Biophysics (10576)
  • Cancer Biology (8173)
  • Cell Biology (11937)
  • Clinical Trials (138)
  • Developmental Biology (6762)
  • Ecology (10401)
  • Epidemiology (2065)
  • Evolutionary Biology (13863)
  • Genetics (9708)
  • Genomics (13070)
  • Immunology (8139)
  • Microbiology (19983)
  • Molecular Biology (7842)
  • Neuroscience (43053)
  • Paleontology (319)
  • Pathology (1279)
  • Pharmacology and Toxicology (2258)
  • Physiology (3351)
  • Plant Biology (7232)
  • Scientific Communication and Education (1312)
  • Synthetic Biology (2004)
  • Systems Biology (5537)
  • Zoology (1128)