title: The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA.
abstract: EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR-124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America. vsenyuk@uic.edu
authors.forename: Vitalyi
authors.initials: V
authors.lastname: Senyuk
authors.forename: Kavitha
authors.initials: K
authors.lastname: Premanand
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Qian
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Nucifora
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D016678:Genome / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011519:Proto-Oncogenes; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; D035683:MicroRNAs; D015513:Oncogene Proteins; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C499305:Mecom protein, mouse; C540079:Mirn124 microRNA, mouse