JunB mediates enhancer/promoter activity of COL1A2 following TGF-beta induction.
Transcriptional control of the genes coding for collagen type I is regulated by a complex interaction between a distal enhancer and a proximal promoter. In this study, we have dissected the molecular mechanism of this interaction by defining a specific sequence within the enhancer that respond in fibroblasts to transforming growth factor-beta (TGF-beta). We show that TGF-beta activates COL1A2 gene via a non-canonical (Smad-independent) signalling pathway, which requires enhancer/promoter co-operation. This interaction involves exchange of cJun/Jun B transcription factor occupancy of a critical enhancer site resulting in the stabilization of enhancer/promoter coalescence. Moreover, using transgenesis, we show that interference in this mechanism results in the abolition of COL1A2 fibroblast expression in vivo. These data are therefore relevant to the control of collagen type I in vivo both in embryonic development, in adult connective tissue homeostasis, and in tissue repair and scarring pathologies.
Ponticos
Markella
M
Department of Medicine, Centre for Rheumatology, University College London Royal Free Campus, London NW3 2PF, UK.
Harvey
Clare
C
Ikeda
Tetsuro
T
Abraham
David
D
Bou-Gharios
George
G
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D024042:Collagen Type I; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D024042:Collagen Type I; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003094:Collagen