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J. Biol. Chem., Vol. 279, Issue 27, 28789-28797, July 2, 2004

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Methylation in the Core-promoter Region of the Chondromodulin-I Gene Determines the Cell-specific Expression by Regulating the Binding of Transcriptional Activator Sp3^*

Tomoki Aoyama, Takeshi Okamoto, Satoshi Nagayama¶, Koichi Nishijo, Tatsuya Ishibe, Ko Yasura, Tomitaka Nakayama, Takashi Nakamura, and Junya Toguchida||

From the Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan, the Department of Orthopedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan, and the ^¶Department of Surgical Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

Transcriptional regulation of cell- and stage-specific genes is a crucial process in the development of mesenchymal tissues. Here we have investigated the regulatory mechanism of the expression of the chondromodulin-I (ChM-I) gene, one of the chondrocyte-specific genes, in osteogenic cells using osteosarcoma (OS) cells as a model. Methylation-specific sequence analyses revealed that the extent of methylation in the core-promoter region of the ChM-I gene was correlated inversely with the expression of the ChM-I gene in OS primary tumors and cell lines. 5-Aza-deoxycytidine treatment induced the expression of the ChM-I gene in ChM-I-negative OS cell lines, and the induction of expression was associated tightly with the demethylation of cytosine at -52 (C(-52)) in the middle of an Sp1/3 binding site to which the Sp3, but not Sp1, bound. The replacement of C(-52) with methyl-cytosine or thymine abrogated Sp3 binding and also the transcription activity of the genomic fragment including C(-52). The inhibition of Sp3 expression by small interfering RNA reduced the expression of the ChM-I gene in ChM-I-positive normal chondrocytes, indicating Sp3 as a physiological transcriptional activator of the ChM-I gene. These results suggest that the methylation status of the core-promoter region is one of the mechanisms to determine the cell-specific expression of the ChM-I gene through the regulation of the binding of Sp3.

Received for publication, February 4, 2004 , and in revised form, April 5, 2004.

^* This work was supported in part by grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science and from the Ministry of Health, Labor, and Welfare of Japan. 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: Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-4134; Fax: 81-75-751-4144; E-mail: togjun{at}frontier.kyoto-u.ac.jp.

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