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Molecular and Cellular Biology, April 2003, p. 2645-2657, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2645-2657.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antithetic Effects of MBD2a on Gene Regulation

Hidetoshi Fujita,1,2,3 Ryouji Fujii,1 Satoko Aratani,1,2,3 Tetsuya Amano,1,4 Akiyoshi Fukamizu,2,3 and Toshihiro Nakajima1,5*

Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512,1 Institute of Applied Biochemistry,2 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8572,3 Locomogene, Incorporated, Shibuya-ku, Tokyo 150-0002,4 PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan5

Received 30 August 2002/ Returned for modification 7 October 2002/ Accepted 31 January 2003

DNA methylation is essential for epigenetic gene regulation during development. The cyclic AMP (cAMP)-responsive element (CRE) is found in the promoter of many cAMP-regulated genes and plays important roles in their gene expression. Methylation occurs on the CRE site and results in transcriptional repression via a direct mechanism, that is, prevention by the methyl group of binding of the cAMP-responsive factor CREB to this site. A recent study indicated that the nucleosome is also important in repressing transcription. In this study, we investigated the regulation of transcriptional repression on methylated CRE. We focused on methyl-CpG binding domain protein 2 (MBD2). MBD2 consists of two forms, MBD2a and MBD2b, the latter lacking the N-terminal extension of MBD2a. Unexpectedly, we found that MBD2a, but not MBD2b, promoted activation of the unmethylated cAMP-responsive genes. An in vivo binding assay revealed that MBD2a selectively interacted with RNA helicase A (RHA), a component of CREB transcriptional coactivator complexes. MBD2a and RHA cooperatively enhanced CREB-dependent gene expression. Interestingly, coimmunoprecipitation assays demonstrated that MBD2a binding to RHA was not associated with histone deacetylase 1. Our results indicate a novel role for MBD2a in gene regulation.

* Corresponding author. Mailing address: Department of Genome Science, Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Phone: 81-44-977-8111, ext. 4113. Fax: 81-44-977-9772. E-mail: nakashit{at}marianna-u.ac.jp.

Molecular and Cellular Biology, April 2003, p. 2645-2657, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2645-2657.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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