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 and Chandrasekhar Kanduri ()
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Tanmoy Mondal: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Santhilal Subhash: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Roshan Vaid: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Stefan Enroth: Genetics and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University
Sireesha Uday: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Björn Reinius: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Sanhita Mitra: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Arif Mohammed: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Alva Rani James: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg
Emily Hoberg: University of Gothenburg
Aristidis Moustakas: Science for Life Laboratory, Uppsala University
Ulf Gyllensten: Genetics and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University
Steven J.M. Jones: Genome Sciences Centre, British Columbia Cancer Agency
Claes M Gustafsson: University of Gothenburg
Andrew H Sims: Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research UK Centre
Fredrik Westerlund: Chalmers University of Technology
Eduardo Gorab: Instituto de Biociências, Universidade de São Paulo
Chandrasekhar Kanduri: Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8743

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