DNMT1-interacting RNAs block gene-specific DNA methylation

• Published in: Nature (London) Vol. 503; no. 7476; pp. 371 - 376
• Main Authors: Di Ruscio, Annalisa, Ebralidze, Alexander K., Benoukraf, Touati, Amabile, Giovanni, Goff, Loyal A., Terragni, Jolyon, Figueroa, Maria Eugenia, De Figueiredo Pontes, Lorena Lobo, Alberich-Jorda, Meritxell, Zhang, Pu, Wu, Mengchu, D’Alò, Francesco, Melnick, Ari, Leone, Giuseppe, Ebralidze, Konstantin K., Pradhan, Sriharsa, Rinn, John L., Tenen, Daniel G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2013; Nature Publishing Group
• Subjects: 631/208/176/1988; 631/337/384/2568; Base Sequence; CCAAT-Enhancer-Binding Proteins - genetics; Cell Line; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA - genetics; DNA - metabolism; DNA methylation; DNA Methylation - genetics; Epigenetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation - genetics; Gene loci; Genome, Human - genetics; Genomes; Humanities and Social Sciences; Humans; Methods; Methylation; Methyltransferases; multidisciplinary; Properties; RNA sequencing; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; RNA-Binding Proteins - metabolism; Science; Substrate Specificity; Transcription, Genetic - genetics
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12598

DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1–RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases. RNAs are shown to interact with DNA methyltransferase 1 and prevent DNA methylation of genes at their specific locus, providing evidence that active transcription directly regulates DNA methylation levels. DNA methylation blocked by non-coding RNA DNA methylation is an epigenetic modification associated with silencing of gene expression. Here, Daniel Tenen and colleagues propose that active transcription directly regulates levels of DNA methylation. A non-coding RNA arising from the well-studied methylation-sensitive gene CEBPA interacts with the DNA methyltransferase DNMT1 to prevent methylation at the CEBPA locus, thereby facilitating CEBPA expression. Functional associations between DNMT1 and RNAs seem to occur at numerous gene loci. These findings support the hypothesis that non-coding RNA participates in the regulation of genomic methylation patterns by interacting with DNMT1 and suggest a potential therapeutic strategy for site-specific alteration of aberrant DNA methylation.