title: DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences: role of the DNMT3L/DNMT3B/p65-NFκB complex in the (de-)methylation of TRAF1.
abstract: DNMT3L i.e. DNA (cytosine-5)-methyltransferase 3-like protein, is devoid of cytosine methyltransferase activity, despite clear homology to DNMT3A and DNMT3B, due to the mutation of key catalytic residues. However, DNMT3L participates in de novo methylation reactions through its direct interaction with DNMT3A and DNMT3B. In the present study, we investigated if DNMT3L interacts also directly with transcription factors (TFs). Using TF arrays, we identified 73 TFs that interacted with DNMT3L, 13 of which (ASH2L, ATF1, ATF3, BLZF1, CDX2, CERM, E2F3, E2F4, GCNF, GTF2I, GTF3C5, NFkB-p65 and RXRα) interacted only with DNMT3L, but not with DNMT3A/B. By focusing on the interaction with NFkB-p65, we demonstrate that DNMT3L forms a complex with DNMT3B and NFkB-p65 and that this complex is required for the control of DNA methylation at the TRAF1 promoter in the T98G glioma cell line. In addition, our experiments describe the DNA methylation at TRAF1 as being dynamic with a demethylation phase involving TET3. Thus, our data suggests that DNMT3L can address DNMT3A/B to specific sites by directly interacting with TFs that do not directly interact with DNMT3A/B. In summary, our data provide a new avenue for the direction of site-specific de novo DNA methylation catalyzed by DNMT3A/B.
authors: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 Quai Moncousu, BP7021, 44007 Nantes, France; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-44000 Nantes, France.
authors: Romain
authors: R
authors: Pacaud
authors: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 Quai Moncousu, BP7021, 44007 Nantes, France; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-44000 Nantes, France.
authors: Quentin
authors: Q
authors: Sery
authors: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 Quai Moncousu, BP7021, 44007 Nantes, France; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-44000 Nantes, France.
authors: Lisa
authors: L
authors: Oliver
authors: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 Quai Moncousu, BP7021, 44007 Nantes, France; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-44000 Nantes, France; Institut de Cancérologie de l'Ouest - LaBCT, René Gauducheau, Boulevard J. Monod, F-44805 St Herblain, France.
authors: François M
authors: FM
authors: Vallette
authors: Laboratory for Epigenetics and Environnement, Centre National de Génotypage, CEA - Institut de Génomique, F-91000 Evry, France.
authors: Jörg
authors: J
authors: Tost
authors: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 Quai Moncousu, BP7021, 44007 Nantes, France; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-44000 Nantes, France; Institut de Cancérologie de l'Ouest - LaBCT, René Gauducheau, Boulevard J. Monod, F-44805 St Herblain, France; Membre du réseau Epigénétique du Cancéropole Grand Ouest, France. Electronic address: pierre-francois.cartron@univ-nantes.fr.
authors: Pierre-François
authors: PF
authors: Cartron
mesh_terms: D001483:Base Sequence; D055162:Biocatalysis; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D013379:Substrate Specificity; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D047990:TNF Receptor-Associated Factor 1; D051996:Transcription Factor RelA; D000097584:DNA Methyltransferase 3B; C412484:DNMT3L protein, human
keywords: Apoptosis; DNA methylation; DNMT3; DNMT3L; Epigenetic; TRAF1