Lee Bomi, Wu Cheng-Ying, Lin Yi-Wei, Park Sung Wook, Wei Li-Na
Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
Nucleic Acids Res. 2016 Sep 19;44(16):7568-79. doi: 10.1093/nar/gkw392. Epub 2016 May 10.
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.
全反式维甲酸（RA）及其衍生物是包括伤口修复在内的免疫功能的有效治疗剂。然而，RA在先天免疫中的调节分子机制尚不清楚，尤其是在巨噬细胞中。我们发现局部应用RA可显著改善伤口愈合，并且RA和IL-4在M2极化巨噬细胞中协同激活组织修复的关键基因Arg1。这涉及RA生物合成的限速酶Raldh2的前馈调节，并且需要Med25来协调RAR、STAT6和染色质重塑因子Brg1，以重塑Arg1的+1核小体用于转录起始。通过招募延伸因子TFIIS，Med25还促进转录起始-延伸偶联。本研究揭示了RA和IL-4在M2巨噬细胞中对Arg1的协同激活，这涉及RA合成的前馈调节以及Med25在核小体重塑和转录起始-延伸偶联中的双重功能，这是RA在先天免疫中强大调节活性的基础。
