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

Czimmerer, Z.; Daniel, B.; Horvath, A.; Rückerl, D.; Nagy, G.; Kiss, M.; Peloquin, M.; Budai, M.M.; Cuaranta-Monroy, I.; Simandi, Z.; Steiner, L.; Nagy, B.; Poliska, S.; Banko, C.; Bacso, Z.; Schulman, I.G.; Sauer, S.; Deleuze, J.F.; Allen, J.E.; Benko, S.; Nagy, L.

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., Daniel, B., Horvath, A., Rückerl, D., Nagy, G., Kiss, M., Peloquin, M., Budai, M.M., Cuaranta-Monroy, I., Simandi, Z., Steiner, L., Nagy, B., Poliska, S., Banko, C., Bacso, Z., Schulman, I.G., Sauer, S., Deleuze, J.F., Allen, J.E., 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, Animals, Mice
Source:	Immunity
ISSN:	1074-7613
Volume:	48
Number:	1
Page Range:	75-90
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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