title: Epigenetic silencing of the XAF1 gene is mediated by the loss of CTCF binding.
abstract: XAF1 is a tumour suppressor gene that compromises cell viability by modulating different cellular events such as mitosis, cell cycle progression and apoptosis. In cancer, the XAF1 gene is commonly silenced by CpG-dinucleotide hypermethylation of its promoter. DNA demethylating agents induce transcriptional reactivation of XAF1, sensitizing cancer cells to therapy. The molecular mechanisms that mediate promoter CpG methylation have not been previously studied. Here, we demonstrate that CTCF interacts with the XAF1 promoter in vivo in a methylation-sensitive manner. By transgene assays, we demonstrate that CTCF mediates the open-chromatin configuration of the XAF1 promoter, inhibiting both CpG-dinucleotide methylation and repressive histone posttranslational modifications. In addition, the absence of CTCF in the XAF1 promoter inhibits transcriptional activation induced by well-known apoptosis activators. We report for the first time that epigenetic silencing of the XAF1 gene is a consequence of the loss of CTCF binding.
authors.affiliation: Functional Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, Mexico.
authors.forename: Georgina
authors.initials: G
authors.lastname: Victoria-Acosta
authors.affiliation: Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, México.
authors.forename: Karla
authors.initials: K
authors.lastname: Vazquez-Santillan
authors.affiliation: Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, México.
authors.forename: Luis
authors.initials: L
authors.lastname: Jimenez-Hernandez
authors.affiliation: Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, México.
authors.forename: Laura
authors.initials: L
authors.lastname: Muñoz-Galindo
authors.affiliation: Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, México.
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado
authors.affiliation: Functional Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, Mexico.|Unit of Investigative Research on Oncological Disease, Children's Hospital of Mexico "Federico Gomez", Mexico City, Mexico.
authors.forename: Gustavo Ulises
authors.initials: GU
authors.lastname: Martinez-Ruiz
authors.affiliation: Functional Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico D.F., 14610, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D000076246:CCCTC-Binding Factor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C417551:XAF1 protein, human