GENES: STRUCTURE AND REGULATION
Cbfa1 Contributes to the Osteoblast-specific Expression of type I collagen Genes*

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Type I collagen is composed of two chains, α1(I) and α2(I), encoded by two distinct genes, the α1(I) and α2(I) collagen genes, that are highly expressed in osteoblasts. In most physiological situations, α1(I) and α2(I) collagen expression is coregulated, suggesting that identical transcription factors control their expression. Here, we studied the role of Cbfa1, an osteoblast-specific transcription factor, in the control of α1(I) and α2(I) collagen expression in osteoblasts. A consensus Cbfa1-binding site, termed OSE2, is present at the same location in the α1(I) collagen promoter at approximately −1347 base pairs (bp) of the rat, mouse, and human genes. Cbfa1 can bind to this site, as demonstrated by electrophoretic mobility shift assay (EMSA) and supershift experiments using an anti-Cbfa1 antibody. Mutagenesis of the α1(I) collagenOSE2 at −1347 bp reduced the activity of a α1(I) collagen promoter fragment 2- to 3-fold. Moreover, multimers of this OSE2 at −1347bp confer osteoblast-specific activity to a minimum α1(I) collagen promoter fragment in DNA transfection experiments as well as in transgenic mice. An additional Cbfa1-binding element is present in the α1(I) collagen promoter of mouse, rat, and human at approximately position −372. This site binds Cbfa1 only weakly and does not act as a cis-acting activator of transcription when tested in DNA transfection experiments. Similar to α1(I) collagen, the mouse α2(I) collagen gene contains multiple OSE2 sites, of which one is conserved across multiple species. In EMSA, Cbfa1 binds to this site and multimers of this α2(I) OSE2 element confer osteoblast-specific activity to the minimum α1(I) collagen promoter in DNA transfection experiments. Thus, our results suggest that Cbfa1 is one of the positive regulators of the osteoblast-specific expression of both type I collagengenes.

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Published, JBC Papers in Press, December 5, 2000, DOI 10.1074/jbc.M006215200

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This work was supported by National Institutes of Health Grants R01AR45548 and R01DE11290, March of Dimes Grant F-198-0082, and a grant from Eli Lilly and Co. (to G. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.