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 -