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

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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., Nagy, G., Czimmerer, Z., Horvath, A., Hammers, D.W., Cuaranta-Monroy, I., Poliska, S., Tzerpos, P., Kolostyak, Z., Hays, T.T., Patsalos, A., Houtman, R., Sauer, S., Francois-Deleuze, J., Rastinejad, F., Balint, B.L., 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, Animals, Mice
Source:	Immunity
ISSN:	1074-7613
Publisher:	Cell Press
Volume:	49
Number:	4
Page Range:	615-626
Date:	16 October 2018
Official Publication:	https://doi.org/10.1016/j.immuni.2018.09.005
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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