title: Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity.
abstract: 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.
authors.affiliation: Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Nak-Won
authors.initials: NW
authors.lastname: Choe
authors.forename: Sung-Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Gwang-Hyeon
authors.initials: GH
authors.lastname: Eom
authors.forename: Hee Jo
authors.initials: HJ
authors.lastname: Baek
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.forename: Hoon
authors.initials: H
authors.lastname: Kook
authors.forename: Sang-Beom
authors.initials: SB
authors.lastname: Seo
mesh_terms: D000107:Acetylation; D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor / Q000201:enzymology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000201:enzymology*; D008297:Male; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011487:Protein Conformation; D011496:Protein Methyltransferases; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D006657:Histones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D006655:Histone Deacetylases