title: Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.
abstract: 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.
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitani
authors.forename: Christina
authors.initials: C
authors.lastname: Stuelten
authors.forename: George
authors.initials: G
authors.lastname: McGrady
authors.forename: Ivan
authors.initials: I
authors.lastname: Fuss
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
mesh_terms: 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
chemical_list: 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