title: Myeloid transforming protein Evi1 interacts with methyl-CpG binding domain protein 3 and inhibits in vitro histone deacetylation by Mbd3/Mi-2/NuRD.
abstract: The ecotropic viral integration site 1 ( Evi1) gene encodes a putative transcription regulator, which is aberrantly expressed in acute myeloid leukemias (AML) with chromosomal abnormalities involving the 3q26 locus. Repression and activation of transcriptional control have been reported, but it is currently unclear how Evi1 may evoke these opposing effects. Using a yeast two-hybrid screen, we identified a novel binding partner of Evi1, i.e., methyl binding domain 3b (Mbd3b) protein, a member of the Mi-2/NuRD histone deacetylase complex. Applying in vitro and in vivo assays, we found that Evi1 interacts with Mbd3b but not with other MBD family members Mbd1, -2, and -4 or MeCP2. We show that interaction of Evi1 with Mbd3 requires 40 amino acids that are adjacent and downstream of the methyl binding domain (MBD). We further demonstrate that the first three zinc fingers of Evi1 are needed for Mbd3 interaction. Evi1 acts as a transcriptional repressor when recruited to an active promoter, yet when present in the Mi-2/NuRD complex through Mbd3 interaction, it inhibits the histone deacetylation function of this multiprotein structure. Our data may in part explain how Evi1 could act as a repressor as well as an activator of transcription.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands.
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.forename: Michiel
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Xavier
authors.initials: X
authors.lastname: Le Guezennec
authors.forename: Renee
authors.initials: R
authors.lastname: Beekman
authors.forename: Antoinette
authors.initials: A
authors.lastname: van Hoven
authors.forename: Eric
authors.initials: E
authors.lastname: Bindels
authors.forename: Henk
authors.initials: H
authors.lastname: Stunnenberg
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D008969:Molecular Sequence Data; D011519:Proto-Oncogenes / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000074008:MDS1 and EVI1 Complex Locus Protein; C492013:Mbd3 protein, mouse; C499305:Mecom protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D000251:Adenosine Triphosphatases; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases