title: Imprinting regulator DNMT3L is a transcriptional repressor associated with histone deacetylase activity.
abstract: DNMT3L is a regulator of imprint establishment of normally methylated maternal genomic sequences. DNMT3L shows high similarity to the de novo DNA methyltransferases, DNMT3A and DNMT3B, however, the amino acid residues needed for DNA cytosine methyltransferase activity have been lost from the DNMT3L protein sequence. Apart from methyltransferase activity, Dnmt3a and Dnmt3b serve as transcriptional repressors associating with histone deacetylase (HDAC) activity. Here we show that DNMT3L can also repress transcription by binding directly to HDAC1 protein. We have identified the PHD-like zinc finger of the ATRX domain as a main repression motif of DNMT3L, through which DNMT3L recruits the HDAC activity needed for transcriptional silencing. Furthermore, we show that DNMT3L protein contains an active nuclear localisation signal at amino acids 156-159. These results describe DNMT3L as a co-repressor protein and suggest that a transcriptionally repressed chromatin organisation through HDAC activity is needed for establishment of genomic imprints.
authors.affiliation: Institute of Medical Technology and Department of Pathology, Tampere University Hospital, University of Tampere, FIN-33014 Tampere, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Aapola
authors.forename: Ingrid
authors.initials: I
authors.lastname: Liiv
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D018392:Genomic Imprinting; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019913:Nuclear Localization Signals; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D019913:Nuclear Localization Signals; D012097:Repressor Proteins; C012589:trichostatin A; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases