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

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

Department of Nutritional Science & Food Management

Research output: Contribution to journal › Article › peer-review

242 Scopus citations

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.

Original language	English
Pages (from-to)	604-614
Number of pages	11
Journal	Molecular Cell
Volume	55
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2014.06.031
State	Published - 21 Aug 2014

Bibliographical note

Funding Information:
We thank Oliver Mücke and Jana Petersen for technical assistance. This work was supported by funding from the Helmholtz Foundation, the German Consortium for Cancer Research, and the National Institutes of Health, DE13123 to C.P. and by an ERC senior investigator grant N°249826-“DNAdemethylase” to C.N. I.G.’s work has been supported by the DFG (GR475/22-1, SFB1036), the excellence cluster CellNetworks, and the ERC (N°232645). Melanoma cell line C8161 and pEF-FH-TET1 were kindly provided by Dr. Mary Hendrix (Children’s Hospital of Chicago Research Center) and Dr. Anjana Rao (La Jolla Institute for Allergy and Immunology), respectively.

Access to Document

10.1016/j.molcel.2014.06.031

Cite this

Arab, K., Park, Y. J., Lindroth, A. M., Schäfer, A., Oakes, C., Weichenhan, D., Lukanova, A., Lundin, E., Risch, A., Meister, M., Dienemann, H., Dyckhoff, G., Herold-Mende, C., Grummt, I., Niehrs, C., & Plass, C. (2014). Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Molecular Cell, 55(4), 604-614. https://doi.org/10.1016/j.molcel.2014.06.031

@article{1128ed9c9ea14cb1b525b9c5dc7b87eb,

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.",

author = "Khelifa Arab and Park, {Yoon Jung} and Lindroth, {Anders M.} and Andrea Sch{\"a}fer and Christopher Oakes and Dieter Weichenhan and Annekatrin Lukanova and Eva Lundin and Angela Risch and Michael Meister and Hendrik Dienemann and Gerhard Dyckhoff and Christel Herold-Mende and Ingrid Grummt and Christof Niehrs and Christoph Plass",

note = "Funding Information: We thank Oliver M{\"u}cke and Jana Petersen for technical assistance. This work was supported by funding from the Helmholtz Foundation, the German Consortium for Cancer Research, and the National Institutes of Health, DE13123 to C.P. and by an ERC senior investigator grant N°249826-“DNAdemethylase” to C.N. I.G.{\textquoteright}s work has been supported by the DFG (GR475/22-1, SFB1036), the excellence cluster CellNetworks, and the ERC (N°232645). Melanoma cell line C8161 and pEF-FH-TET1 were kindly provided by Dr. Mary Hendrix (Children{\textquoteright}s Hospital of Chicago Research Center) and Dr. Anjana Rao (La Jolla Institute for Allergy and Immunology), respectively. ",

year = "2014",

month = aug,

day = "21",

doi = "10.1016/j.molcel.2014.06.031",

language = "English",

volume = "55",

pages = "604--614",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "4",

}

Arab, K, Park, YJ, Lindroth, AM, Schäfer, A, Oakes, C, Weichenhan, D, Lukanova, A, Lundin, E, Risch, A, Meister, M, Dienemann, H, Dyckhoff, G, Herold-Mende, C, Grummt, I, Niehrs, C & Plass, C 2014, 'Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A', Molecular Cell, vol. 55, no. 4, pp. 604-614. https://doi.org/10.1016/j.molcel.2014.06.031

TY - JOUR

T1 - Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A

AU - Arab, Khelifa

AU - Park, Yoon Jung

AU - Lindroth, Anders M.

AU - Schäfer, Andrea

AU - Oakes, Christopher

AU - Weichenhan, Dieter

AU - Lukanova, Annekatrin

AU - Lundin, Eva

AU - Risch, Angela

AU - Meister, Michael

AU - Dienemann, Hendrik

AU - Dyckhoff, Gerhard

AU - Herold-Mende, Christel

AU - Grummt, Ingrid

AU - Niehrs, Christof

AU - Plass, Christoph

N1 - Funding Information: We thank Oliver Mücke and Jana Petersen for technical assistance. This work was supported by funding from the Helmholtz Foundation, the German Consortium for Cancer Research, and the National Institutes of Health, DE13123 to C.P. and by an ERC senior investigator grant N°249826-“DNAdemethylase” to C.N. I.G.’s work has been supported by the DFG (GR475/22-1, SFB1036), the excellence cluster CellNetworks, and the ERC (N°232645). Melanoma cell line C8161 and pEF-FH-TET1 were kindly provided by Dr. Mary Hendrix (Children’s Hospital of Chicago Research Center) and Dr. Anjana Rao (La Jolla Institute for Allergy and Immunology), respectively.

PY - 2014/8/21

Y1 - 2014/8/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906791043&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2014.06.031

DO - 10.1016/j.molcel.2014.06.031

M3 - Article

C2 - 25087872

AN - SCOPUS:84906791043

SN - 1097-2765

VL - 55

SP - 604

EP - 614

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this