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

Khelifa Arab; Yoon Jung Park; Anders M Lindroth; Andrea Schäfer; Christopher Oakes; Dieter Weichenhan; Annekatrin Lukanova; Eva Lundin; Angela Risch; Michael Meister; Hendrik Dienemann; Gerhard Dyckhoff; Christel Herold-Mende; Ingrid Grummt; Christof Niehrs; Christoph Plass

doi:10.1016/j.molcel.2014.06.031

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

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

Authors

Khelifa Arab¹, Yoon Jung Park², Anders M Lindroth², Andrea Schäfer³, Christopher Oakes², Dieter Weichenhan², Annekatrin Lukanova⁴, Eva Lundin⁵, Angela Risch⁶, Michael Meister⁷, Hendrik Dienemann⁸, Gerhard Dyckhoff⁹, Christel Herold-Mende¹⁰, Ingrid Grummt¹¹, Christof Niehrs¹², Christoph Plass¹³

Affiliations

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.

PMID: 25087872
DOI: 10.1016/j.molcel.2014.06.031

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / metabolism*
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
CpG Islands / physiology
Cytosine / analogs & derivatives*
Cytosine / metabolism
DNA Methylation / genetics
DNA Methylation / physiology*
DNA Repair / genetics
Gene Expression Regulation, Neoplastic
Genome, Human
HEK293 Cells
Humans
Molecular Sequence Data
Neoplasms / genetics*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Promoter Regions, Genetic / physiology
RNA, Long Noncoding / genetics
RNA, Long Noncoding / physiology*
Thymine DNA Glycosylase / physiology*

Substances

Basic Helix-Loop-Helix Transcription Factors
Cell Cycle Proteins
GADD45A protein, human
Nuclear Proteins
RNA, Long Noncoding
TCF21 protein, human
5-hydroxymethylcytosine
5-Methylcytosine
Cytosine
Thymine DNA Glycosylase

Associated data

GENBANK/KF484511
GENBANK/KF484512
GENBANK/KF484513
GENBANK/KF484514
GENBANK/KF484515