Nucleic Acids Research Advance Access published online on June 26, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp544
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Molecular Biology |
JunB mediates enhancer/promoter activity of COL1A2 following TGF-β induction
1Department of Medicine, Centre for Rheumatology, University College London (Royal Free Campus) Rowland Hill Street, London NW3 2PF and 2Kennedy Institute of Rheumatology, Imperial College London, 65 Aspenlea Road, London W6 8LH, UK
*To whom correspondence should be addressed. Tel: 02083834413; Fax: 02083834499; Email: g.gharios{at}imperial.ac.uk
Received January 26, 2009. Revised June 6, 2009. Accepted June 10, 2009.
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-β (TGF-β). We show that TGF-β 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.
The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint First Authors.