title: Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A.
abstract: DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
authors.affiliation: Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Khelifa
authors.initials: K
authors.lastname: Arab
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Lindroth
authors.affiliation: Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Oakes
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden.
authors.forename: Annekatrin
authors.initials: A
authors.lastname: Lukanova
authors.affiliation: Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Lundin
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany; Translational Research Unit, Thoraxklinik-Heidelberg gGmbH University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany; Department of Thoracic Surgery, Thoraxklinik-Heidelberg gGmbH, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Division of Molecular Biology of the Cell II, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. Electronic address: i.grummt@dkfz.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Grummt
authors.affiliation: Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. Electronic address: c.niehrs@imb-mainz.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; The German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: c.plass@dkfz.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000502:physiology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000502:physiology*; D044502:Thymine DNA Glycosylase / Q000502:physiology*; D000097642:GADD45 Proteins
chemical_list: D044503:5-Methylcytosine; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D003596:Cytosine; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D044502:Thymine DNA Glycosylase; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C491825:TCF21 protein, human; C011865:5-hydroxymethylcytosine