Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arginase / genetics*
  • Arginase / metabolism
  • Chromatin Assembly and Disassembly / genetics*
  • Inflammation / pathology
  • Interleukin-4 / pharmacology*
  • Macrophage Activation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mediator Complex / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nucleosomes / drug effects
  • Nucleosomes / metabolism
  • RAW 264.7 Cells
  • Receptors, Retinoic Acid / metabolism
  • STAT6 Transcription Factor / metabolism
  • Transcription Elongation, Genetic / drug effects*
  • Transcription Initiation, Genetic / drug effects*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics*
  • Tretinoin / pharmacology*
  • Wound Healing / drug effects


  • Mediator Complex
  • Nucleosomes
  • Receptors, Retinoic Acid
  • STAT6 Transcription Factor
  • Interleukin-4
  • Tretinoin
  • Arg1 protein, mouse
  • Arginase