The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages.

Autor:	Czimmerer Z; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Daniel B; Sanford-Burnham-Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA., Horvath A; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Rückerl D; Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK., Nagy G; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; MTA-DE 'Lendület' Immunogenomics Research Group, University of Debrecen, Debrecen, Hungary., Kiss M; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Peloquin M; Sanford-Burnham-Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA., Budai MM; Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Cuaranta-Monroy I; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Simandi Z; Sanford-Burnham-Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA., Steiner L; UD-Genomed Medical Genomic Technologies Ltd., Debrecen, Hungary., Nagy B Jr; Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Poliska S; Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Banko C; Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Bacso Z; Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Schulman IG; Department of Pharmacology, University of Virginia, Charlottesville, VA, USA., Sauer S; Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany; CU Systems Medicine, University of Würzburg, Würzburg, Germany; Max Delbrück Center for Molecular Medicine (BIMSB and BIH), Berlin, Germany., Deleuze JF; Centre National de Génotypage, Institut de Génomique, CEA, Evry, France., Allen JE; Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK., Benko S; Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Nagy L; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Sanford-Burnham-Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA; MTA-DE 'Lendület' Immunogenomics Research Group, University of Debrecen, Debrecen, Hungary. Electronic address: lnagy@sbpdiscovery.org.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2018 Jan 16; Vol. 48 (1), pp. 75-90.e6.
DOI:	10.1016/j.immuni.2017.12.010
Abstrakt:	The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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