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Mol Cell. 2014 Aug 21;55(4):604-14. doi: 10.1016/j.molcel.2014.06.031. Epub 2014 Jul 31.

Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A.

Author information

1
Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
3
Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
4
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden.
5
Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden.
6
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.
7
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.
8
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.
9
Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
10
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.
11
Division of Molecular Biology of the Cell II, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. Electronic address: i.grummt@dkfz.de.
12
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.
13
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.

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.

PMID:
25087872
DOI:
10.1016/j.molcel.2014.06.031
[Indexed for MEDLINE]
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