Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I

Immunity. 2010 Sep 24;33(3):313-25. doi: 10.1016/j.immuni.2010.09.001.


The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-β (TGF-β)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-β-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer I). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dominant site in enhancer I and a subordinate site in the promoter. This led to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSmad3. Cytokine (IL-27) inhibition involved binding of pStat3 to a gene silencer in a second conserved enhancer region (enhancer II) downstream from enhancer I; this led to loss of pSmad3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-β-induced Foxp3 transcription.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Binding Sites
  • Enhancer Elements, Genetic*
  • Female
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation*
  • Mice
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / physiology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Transforming Growth Factor beta / physiology
  • Retinoid X Receptors / physiology
  • Smad3 Protein / metabolism*
  • Transcription Factor AP-1 / physiology
  • Transcription, Genetic
  • Transforming Growth Factor beta / physiology
  • Tretinoin / pharmacology


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • NFATC Transcription Factors
  • Receptors, Antigen, T-Cell
  • Receptors, Transforming Growth Factor beta
  • Retinoid X Receptors
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Tretinoin
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I