DNMT1-interacting RNAs block gene-specific DNA methylation

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 tha...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These two authors equally contributed to the work
ISSN:	0028-0836 1476-4687
DOI:	10.1038/nature12598