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Molecular and Cellular Biology, March 2008, p. 2023-2034, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.02130-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Multiple Myeloma-Related WHSC1/MMSET Isoform RE-IIBP Is a Histone Methyltransferase with Transcriptional Repression Activity{triangledown}

Ji-Young Kim,1 Hae Jin Kee,2 Nak-Won Choe,2 Sung-Mi Kim,1 Gwang-Hyeon Eom,2 Hee Jo Baek,3 Hyun Kook,2 Hoon Kook,3* and Sang-Beom Seo1*

Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756,1 Medical Research Center for Gene Regulation and Department of Pharmacology,2 Department of Pediatrics, Chonnam National University Medical School, Gwang-ju 501-746, South Korea3

Received 29 November 2007/ Accepted 23 December 2007

Histone methylation is crucial for transcriptional regulation and chromatin remodeling. It has been suggested that the SET domain containing protein RE-IIBP (interleukin-5 [IL-5] response element II binding protein) may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in these 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 we characterized the histone H3 lysine 27 (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 histone deacetylase (HDAC) recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP overexpression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypoacetylation 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.

* Corresponding author. Mailing address for Sang-Beom Seo: Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, South Korea. Phone: 82 2 820 5242. Fax: 82 2 822 3059. E-mail: sangbs{at}cau.ac.kr. Mailing address for Hoon Kook: Department of Pediatrics, Chonnam National University Medical School, Gwangju 501-746, South Korea. Phone: 82-61-379-7693. Fax: 82-61-379-7697. E-mail: hoonkook{at}chonnam.ac.kr

{triangledown} Published ahead of print on 2 January 2008.

Molecular and Cellular Biology, March 2008, p. 2023-2034, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.02130-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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