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The transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages

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Item Type:Article
Title:The transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages
Creators Name:Czimmerer, Z. and Daniel, B. and Horvath, A. and Rückerl, D. and Nagy, G. and Kiss, M. and Peloquin, M. and Budai, M.M. and Cuaranta-Monroy, I. and Simandi, Z. and Steiner, L. and Nagy, B. and Poliska, S. and Banko, C. and Bacso, Z. and Schulman, I.G. and Sauer, S. and Deleuze, J.F. and Allen, J.E. and Benko, S. and Nagy, L.
Abstract: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.
Keywords:IL-4, STAT6, Alternative Macrophage Polarization, Transcription, Repression, Inflammation, Inflammasome Activation, Pyroptosis, IL-1β, Macrophage Epigenomics
Source:Immunity
ISSN:1074-7613
Volume:48
Number:1
Page Range:75-90.e6
Date:16 January 2018
Official Publication:https://doi.org/10.1016/j.immuni.2017.12.010
PubMed:View item in PubMed

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