Regulation of collagen type I in vascular smooth muscle cells by competition between Nkx2.5 and deltaEF1/ZEB1.
A major component of the vessel wall of large arteries and veins is the extracellular matrix (ECM), which consists of collagens, elastin, and proteoglycans. Collagen type I is one of the most abundant of the ECM proteins. We have previously shown that the pro-collagen type I alpha 2 gene contains an enhancer which confers tissue-specific expression in the majority of collagen-producing cells, including blood vessels. In this paper, we delineate a specific vascular smooth muscle cell (vSMC) element: a 100-bp sequence around -16.6 kb upstream of the transcription start site that regulates collagen expression exclusively in vSMCs. Furthermore, we show that the expression is activated through the binding of the homeodomain protein Nkx2.5, which is further potentiated in the presence of GATA6. In contrast, this element was repressed by the binding of the zinc-finger protein deltaEF1/ZEB1. We propose a model of regulation where the activating transcription factor Nkx2.5 and the repressor deltaEF1/ZEB1 compete for an overlapping DNA binding site. This element is important in understanding the molecular mechanisms of vessel remodeling and is a potential target for intervention in vascular diseases where there is excessive deposition of collagen in the vessel wall.
Ponticos
Markella
M
Centre for Rheumatology, Department of Medicine, University College of London, United Kingdom.
Partridge
Terrence
T
Black
Carol M
CM
Abraham
David J
DJ
Bou-Gharios
George
G
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D050993:GATA6 Transcription Factor; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016335:Zinc Fingers
D024042:Collagen Type I; D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C494759:GATA6 protein, human; C494760:Gata6 protein, mouse; C484469:Nkx2-5 protein, mouse; C486307:ZEB1 protein, human; C000630720:ZEB1 protein, rat; C519422:ZEB1 protein, mouse