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The nuclear receptor PPARγ controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory

Item Type:Article
Title:The nuclear receptor PPARγ controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory
Creators Name:Daniel, B. and Nagy, G. and Czimmerer, Z. and Horvath, A. and Hammers, D.W. and Cuaranta-Monroy, I. and Poliska, S. and Tzerpos, P. and Kolostyak, Z. and Hays, T.T. and Patsalos, A. and Houtman, R. and Sauer, S. and Francois-Deleuze, J. and Rastinejad, F. and Balint, B.L. and Sweeney, H.L. and Nagy, L.
Abstract:Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization.
Keywords:Nuclear Receptor, PPARγ, Coregulators, Ligand-Insensitive Enhancers, Epigenomics, Transcriptional Memory, Progressive Polarization, Macrophage Polarization, IL-4, IFN-γ, Muscle Regeneration
Source:Immunity
ISSN:1074-7613
Publisher:Cell Press (U.S.A.)
Volume:49
Number:4
Page Range:615-626
Date:16 October 2018
Official Publication:https://doi.org/10.1016/j.immuni.2018.09.005
PubMed:View item in PubMed

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