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Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>\n                    Homeostatic macrophages maintain tissue health and resolve inflammation. Upon sustained exposure to type II cytokine IL4, transcription factors STAT6, KLF4, EGR2 and a ligand-regulated nuclear receptor PPAR\u03b3 orchestrate the M2\n                    <jats:sub>IL4<\/jats:sub>\n                    \u2018polarization\u2019, marked by enhancer RNA (eRNA) production near multiple M2 genes. The mechanisms of enhancer activation by unliganded PPAR\u03b3 are poorly understood. We interrogated cofactor requirements for PPAR\u03b3-driven gene expression in M2\n                    <jats:sub>IL4<\/jats:sub>\n                    , including those lacking PPAR\u03b3 or a ligand-dependent nuclear receptor coregulator NCoA2\/GRIP1 vs. macrophages treated with the PPAR\u03b3 agonist rosiglitazone. As expected, rosiglitazone activated conventional PPAR\u03b3 targets; GRIP1 deletion blunted their induction and depleted GRIP1-interacting histone acetyltransferase p300 from PPAR\u03b3-bound sites. Surprisingly, GRIP1 colocalized with unliganded PPAR\u03b3 in M0 and M2\n                    <jats:sub>IL4<\/jats:sub>\n                    , and GRIP1 ablation dramatically reduced genome-wide DNA binding of PPAR\u03b3 itself while promoting broad deposition of CTCF insulator. Functionally, GRIP1 deletion mirrored PPAR\u03b3 deficiency, establishing GRIP1 as a central regulator of unliganded PPAR\u03b3 DNA binding, required for both eRNA and mRNA transcription of PPAR\u03b3 targets in homeostatic macrophages.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh4524","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:59:24Z","timestamp":1792000764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A transcriptional cofactor GRIP1 drives PPAR\u03b3 DNA binding and p300-dependent enhancer activity during homeostatic macrophage polarization"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9624-5049","authenticated-orcid":true,"given":"Marija","family":"Dacic","sequence":"first","affiliation":[{"name":"Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, New York, NY, 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