BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • O'Connor, Michelle Hoffner
    • Affiliation: School of Medicine, Department of Genetics
  • Berglind, Ana
    • Affiliation: School of Medicine, Department of Genetics
  • Ng, Meaghan M. Kennedy
    • Affiliation: School of Medicine, Department of Genetics
  • Keith, Benjamin P.
    • Affiliation: School of Medicine, Department of Genetics
  • Lynch, Zachary J.
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Schaner, Matthew R.
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Steinbach, Erin C.
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Herzog, Jeremy
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Trad, Omar K.
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Jeck, William R.
    • Other Affiliation: Duke University
  • Arthur, Janelle C.
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Simon, Jeremy M.
    • Affiliation: School of Medicine, Department of Genetics
  • Sartor, R. Balfour
    • Affiliation: Center for Gastrointestinal Biology and Disease
  • Furey, Terrence S.
    • Affiliation: School of Medicine, Department of Genetics
  • Sheikh, Shehzad Z.
    • Affiliation: School of Medicine, Department of Genetics
Abstract
  • Introduction In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate 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 and absence of lipopolysaccharide (LPS) with and 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 attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity 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.
Date of publication
Keyword
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
License
  • Attribution 4.0 International
Journal title
  • Frontiers in Immunology
Journal volume
  • 13
Language
  • English
Version
  • Publisher
ISSN
  • 1664-3224

Relations

Parents:

This work has no parents.

In Collection:

Items

Thumbnail Title Date Uploaded Visibility Actions
file details fimmu-13-856966.pdf 2022-03-28 Public Download