LAUSR

Graphical Abstract Figure. No caption available. SUMMARY Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPAR&ggr; drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)‐4. The functions of PPAR&ggr; on macrophage polarization in this setting were independent of ligand binding. Ligand‐insensitive PPAR&ggr; 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 PPAR&ggr; 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 PPAR&ggr; in the affected tissue. Thus, a predominantly ligand‐insensitive PPAR&ggr;:RXR cistrome regulates progressive and/or reinforcing macrophage polarization. HIGHLIGHTSLigand‐insensitive PPAR&ggr; sites are highly abundant in alternatively polarized MQsPPAR&ggr; is recruited to the genome in a ligand‐independent manner upon polarizationLigand‐insensitive PPAR&ggr; alters chromatin structure and facilitates IL‐4 signalingLigand‐insensitive PPAR&ggr; drives progressive polarization via transcriptional memory &NA; Daniel et al. describe that the nuclear receptor PPAR&ggr; has a significant ligand‐insensitive, genome‐bound fraction that affects local chromatin structure upon macrophage polarization. Ligand‐insensitive PPAR&ggr; mediates the expression of a hidden gene set upon repeated IL‐4 exposure, providing transcriptional memory and an epigenomic ratchet mechanism to support progressive polarization.