title: Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling.
abstract: All-trans Retinoic acid (RA) and its derivatives are potent therapeutics for immunological functions including wound repair. However, the molecular mechanism of RA modulation in innate immunity is poorly understood, especially in macrophages. We found that topical application of RA significantly improves wound healing and that RA and IL-4 synergistically activate Arg1, a critical gene for tissue repair, in M2 polarized macrophages. This involves feed forward regulation of Raldh2, a rate-limiting enzyme for RA biosynthesis, and requires Med25 to coordinate RAR, STAT6 and chromatin remodeler, Brg1 to remodel the +1 nucleosome of Arg1 for transcription initiation. By recruiting elongation factor TFIIS, Med25 also facilitates transcriptional initiation-elongation coupling. This study uncovers synergistic activation of Arg1 by RA and IL-4 in M2 macrophages that involves feed forward regulation of RA synthesis and dual functions of Med25 in nucleosome remodeling and transcription initiation-elongation coupling that underlies robust modulatory activity of RA in innate immunity.
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bomi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA weixx009@umn.edu.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D007249:Inflammation / Q000473:pathology; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D056892:Mediator Complex / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D000067996:RAW 264.7 Cells; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D061805:Transcription Elongation, Genetic / Q000187:drug effects*; D061785:Transcription Initiation, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D056892:Mediator Complex; D009707:Nucleosomes; D018168:Receptors, Retinoic Acid; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D014212:Tretinoin; C544448:Arg1 protein, mouse; D001119:Arginase