Long non-coding RNA targets DNA demethylation

Orateur : Khelifa ARAB (DKFZ, Heidelberg, Allemagne)

Non-coding RNAs are a large diversified family of transcripts, which can be classified by : size, function or cellular localization. Although lowly conserved between species, long non-coding RNAs (lncRNAs) exhibit cell- and tissues-specific expression even more so than messenger RNAs, suggesting functions in cell fate decision. LncRNA emerged recently as key players in epigenetic reprogramming and genome regulation. However for many lncRNAs their function are still unknown. We have discovered and characterized a lncRNA termed TARID (Transcription Factor 21 antisense RNA inducing demethylation). TARID is a TCF21 antisense lncRNA that reactivates the tumor suppressor TCF21 by repressing aberrant promoter DNA methylation and promoting a permissive chromatin state. TARID interacts physically with TCF21 promoter and triggers the targeting of the DNA demethylation machinery via GADD45a (Growth arrest and DNA-damage inducible alpha). The dynamic process of TCF21 promoter DNA demethylation requires a DNA repair step after TET (Ten-eleven translocation methylcytosine dioxygenase 1) mediated oxidation of 5-methylcytosine. The base excision repair machinery involving TDG (thymine DNA glycosylase) removes oxidized 5-methylcytosine bases and repairs the lesions by unmethylated cytosines. We conclude that TARID is serving as an adapter to link the DNA demethylation complex and target the proteins specifically to TCF21 promoter sequences. Our results rises a novel hypothesis that lncRNA may serve as genomic address labels to target the DNA demethylation machinery to specific gene loci. Taken together, our work put lights on the mechanisms of gene inactivation/reactivation during tumor development.

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