Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity.
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.
Kim
Ji-Young
JY
Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, South Korea.
Kee
Hae Jin
HJ
Choe
Nak-Won
NW
Kim
Sung-Mi
SM
Eom
Gwang-Hyeon
GH
Baek
Hee Jo
HJ
Kook
Hyun
H
Kook
Hoon
H
Seo
Sang-Beom
SB
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
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