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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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