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J. Biol. Chem., Vol. 280, Issue 22, 21004-21014, June 3, 2005

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Collagen 1(I) Gene (COL1A1) Is Repressed by RFX Family^*

Pritam Sengupta, Yong Xu, Lin Wang, Russell Widom¶, and Barbara D. Smith||

From the Department of Biochemistry and ^¶Arthritis Center, Boston University School of Medicine, Boston, Massachusetts 02118 and the Veterans Affairs Boston Healthcare System, Boston, Massachusetts 02118

Collagen type I is composed of three polypeptide chains transcribed from two separate genes (COL1A1 and COL1A2) with different promoters requiring coordinate regulation. Our recent publications, centering on COL1A2 regulation, demonstrate that methylation in the first exon of COL1A2 at a regulatory factor for X box (RFX) site (at –1 to +20) occurs in human cancer cells and correlates with increased RFX1 binding and decreased collagen transcription (Sengupta, P. K., Erhlich, M., and Smith, B. D. (1999) J. Biol. Chem. 274, 36649–36655; Sengupta, S., Smith, E. M., Kim, K., Murnane, M. J., and Smith, B. D. (2003) Cancer Res. 63, 1789–1797). In normal cells, RFX5 complex along with major histocompatibility class II transactivator (CIITA) is induced by interferon- to occupy this site and repress collagen transcription (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319–41332). In this paper, we demonstrate that COL1A1 has an RFX consensus binding site surrounding the transcription start site (–11 to +10) that contains three methylation sites rather than one in the COL1A2 gene RFX binding site. RFX1 interacts weakly with the unmethylated COL1A1 site, and binds with higher affinity to the methylated site. RFX1 represses the unmethylated COL1A1 less efficiently than COL1A2. COL1A1 promoter activity is sensitive to DNA methylation and the COL1A1 gene is methylated in human cancer cells with coordinately decreased collagen expression. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (aza-dC) increases collagen gene expression with time in human cancer cells. On the other hand, RFX5 interacts with both collagen type I genes with a similar binding affinity and represses both promoters equally in transient transfections. Two dominant negative forms of RFX5 activate both collagen genes coordinately. Finally, CIITA RNA interference experiments indicate that CIITA induction is required for interferon -mediated repression of both collagen type I genes.

Received for publication, November 22, 2004 , and in revised form, March 7, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4159; Fax: 617-638-5339; E-mail: smith{at}biochem.bumc.bu.edu.

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