Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.
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.
Xu
Lili
L
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kitani
Atsushi
A
Stuelten
Christina
C
McGrady
George
G
Fuss
Ivan
I
Strober
Warren
W
D000818:Animals; D001665:Binding Sites; D004742:Enhancer Elements, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D047488:Retinoid X Receptors / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D018125:Receptors, Transforming Growth Factor beta; D047488:Retinoid X Receptors; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I