MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures

Tanmoy Mondal, Santhilal Subhash, Roshan Vaid, Stefan Enroth, Sireesha Uday, Björn Reinius, Sanhita Mitra, Arif Mohammed, Alva Rani James, Emily Hoberg, Aristidis Moustakas, Ulf Gyllensten, Steven J M Jones, Claes M Gustafsson, Andrew H Sims, Fredrik Westerlund, Eduardo Gorab, Chandrasekhar Kanduri

Research output: Contribution to journalArticlepeer-review

Abstract

Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation. We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

Original languageEnglish
Pages (from-to)7743
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 24 Jul 2015

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