Mol. Cell 55, 604–614 (2014)

DNA methylation is a reversible epigenetic process that is associated with transcriptional repression. Methyl groups are installed at the C5 positions of cytosines in CpG-rich sequences by DNA methyltransferase enzymes, but the machineries that remove these marks remain incompletely characterized. Arab et al. now provide evidence that gene-specific DNA demethylation may be directed by long noncoding RNAs (lncRNAs) and adaptor proteins that recruit the DNA demethylation apparatus. Following up on their earlier studies of the tumor suppressor, transcription factor 21 (TCF21), the authors discovered a promoter at a downstream CpG island within the TCF21 gene that expresses a 4.5-kb RNA nuclear antisense transcript that has features of a lncRNA. Expression of this transcript, termed TCF21 antisense RNA inducing demethylation (TARID), leads to decreased DNA methylation at the transcriptional start site (TSS) of TCF21 and increased expression of TCF21 mRNA. Immunoprecipitation studies revealed that TARID binds GADD45A, an RNA-binding protein known to regulate DNA demethylation, and also the TCF21 promoter through a complementary antisense interaction with TSS sequences. Further biochemical experiments showed that this ribonucleoprotein complex recruits two enzymes linked to active DNA demethylation—thymine DNA glycosylase and ten-eleven translocation methylcytosine dioxygenase—to the TCF21 promoter. Taken together, these data suggest that TARID, and perhaps other lncRNAs, may serve as sequence-specific bar codes to address the DNA demethylation machinery to specific gene loci.