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Mol. Cell. Biol. doi:10.1128/MCB.02130-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Multiple myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity

Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756; Medical Research Center for Gene Regulation and Departments of Pharmacology and Pediatrics, Chonnam National University Medical School, Gwang-ju, 501-746, Korea

^* To whom correspondence should be addressed. Email: hoonkook{at}chonnam.ac.kr. sangbs{at}cau.ac.kr.

	Abstract

Histone methylation is crucial for transcriptional regulation and chromatin remodeling. The SET-domain containing protein RE-IIBP (interleukin-5 response element II binding protein) has been suggested that it may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in those diseases remains to be clearly elucidated. In this study, we have conducted an investigation into the relationship between the histone-methylating activity of RE-IIBP and transcriptional regulation. Here, we report that RE-IIBP is up-regulated in the blood cells of leukemia patients, and characterized the H3-K27 methyltransferase activity of RE-IIBP. Point mutant analysis revealed that SET-domain cysteine 483 and arginine 477 are critical residues for the Histone Methyltransferase (HMTase) activity of RE-IIBP. RE-IIBP also represses basal transcription via HDAC recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP over-expression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypo-acetylation on the IL-5 promoter and represses expression. Conversely, short hairpin RNA-mediated knockdown of RE-IIBP reduces histone H3-K27 methylation and HDAC occupancy around the IL-5 promoter. These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis.