PMID- 35401533 OWN - NLM STAT- MEDLINE DCOM- 20220412 LR - 20230405 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis. PG - 856966 LID - 10.3389/fimmu.2022.856966 [doi] LID - 856966 AB - 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. CI - Copyright (c) 2022 Hoffner O'Connor, Berglind, Kennedy Ng, Keith, Lynch, Schaner, Steinbach, Herzog, Trad, Jeck, Arthur, Simon, Sartor, Furey and Sheikh. FAU - Hoffner O'Connor, Michelle AU - Hoffner O'Connor M AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Berglind, Ana AU - Berglind A AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Kennedy Ng, Meaghan M AU - Kennedy Ng MM AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Keith, Benjamin P AU - Keith BP AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Lynch, Zachary J AU - Lynch ZJ AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Schaner, Matthew R AU - Schaner MR AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Steinbach, Erin C AU - Steinbach EC AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Herzog, Jeremy AU - Herzog J AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Trad, Omar K AU - Trad OK AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Jeck, William R AU - Jeck WR AD - Department of Pathology, Duke University, Durham, NC, United States. FAU - Arthur, Janelle C AU - Arthur JC AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Simon, Jeremy M AU - Simon JM AD - Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Carolina Institute for Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Sartor, R Balfour AU - Sartor RB AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Furey, Terrence S AU - Furey TS AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Sheikh, Shehzad Z AU - Sheikh SZ AD - Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. AD - Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. LA - eng GR - P01 DK094779/DK/NIDDK NIH HHS/United States GR - R01 DK124617/DK/NIDDK NIH HHS/United States GR - P40 OD010995/OD/NIH HHS/United States GR - F31 DK122704/DK/NIDDK NIH HHS/United States GR - P30 DK034987/DK/NIDDK NIH HHS/United States GR - T32 GM007092/GM/NIGMS NIH HHS/United States GR - R01 DK104828/DK/NIDDK NIH HHS/United States GR - T32 DK007737/DK/NIDDK NIH HHS/United States GR - T32 GM122741/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220324 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Chromatin) RN - 0 (Dner protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Transcription Factors) RN - 130068-27-8 (Interleukin-10) SB - IM MH - Animals MH - Chromatin/genetics/metabolism MH - *Colitis/chemically induced/metabolism MH - Interleukin-10/genetics/metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/metabolism MH - Mice MH - *Microbiota MH - Nerve Tissue Proteins MH - Receptors, Cell Surface MH - Transcription Factors/metabolism PMC - PMC8988134 OTO - NOTNLM OT - Crohn's disease OT - chromatin OT - inflammation OT - macrophage OT - regulation COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/04/12 06:00 MHDA- 2022/04/13 06:00 PMCR- 2022/01/01 CRDT- 2022/04/11 05:28 PHST- 2022/01/17 00:00 [received] PHST- 2022/02/16 00:00 [accepted] PHST- 2022/04/11 05:28 [entrez] PHST- 2022/04/12 06:00 [pubmed] PHST- 2022/04/13 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.856966 [doi] PST - epublish SO - Front Immunol. 2022 Mar 24;13:856966. doi: 10.3389/fimmu.2022.856966. eCollection 2022.