Col1a2 enhancer regulates collagen activity during development and in adult tissue repair

• Published in: Matrix biology 2004-02, Vol.22 (8), p.619-628
• Main Authors: Ponticos, Markella, Abraham, David, Alexakis, Catherine, Lu, Qi-Long, Black, Carol, Partridge, Terence, Bou-Gharios, George
• Format: Article
• Language: English
• Subjects: Animals; Collagen - genetics; Collagen - metabolism; Collagen Type I; Connective tissue; Embryo, Mammalian - anatomy & histology; Embryo, Mammalian - physiology; Embryonic development; Enhancer; Enhancer Elements, Genetic; Female; Fibrosis; Gene Expression Regulation, Developmental; Genes, Reporter; Gestational Age; Humans; In Situ Hybridization; Kidney - anatomy & histology; Kidney - metabolism; Kidney - pathology; Lung - anatomy & histology; Lung - metabolism; Lung - pathology; Mice; Mice, Transgenic; Muscle, Skeletal - anatomy & histology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Pregnancy; Skin - anatomy & histology; Skin - drug effects; Skin - metabolism; Skin - pathology; Transcription, Genetic; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2003.12.002

An enhancer region in the type I collagen alpha 2 chain (pro- Col1a2) promoter has been previously identified approximately −17 kb away from the transcription start site. This upstream region termed the far-upstream-enhancer contains three DNAse I hypersensitive sites and has been shown to be conserved between mouse and human genes. In this study, we used transgenic mice harbouring the complete promotor sequence of the pro- Col1a2 gene up to −17 kb to examine the role of this enhancer in the expression and regulation of the collagen gene during development and in adult tissues pre and post injury. By careful histological mapping of the collagen type I endogenous gene distribution with that of the transgene driven by the mouse far upstream enhancer, we are able to show that in early days of collagen expression, E8.5-9.5, the endogenous gene preceded transgene expression. However, by E11.5 the overall pattern becomes synchronous with a few exceptions. In adult tissue, both endogenous and transgene expression are attenuated and both are reactivated in parallel in various organs by physical injury or fibrogenic cytokine injection. These findings suggest that the enhancer is central to the activation of the collagen type I and that mice harbouring this enhancer/reporter provide a useful model to follow collagen gene transcription activity and for investigating cellular activity in tissue fibrosis.