MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures
Authors: Arif Mohammed
Chandrasekhar Kanduri
Fredrik Westerlund
Emily Hoberg
Roshan Vaid
Claes M Gustafsson
Sanhita Mitra
Steven J M Jones
Ulf Gyllensten
Tanmoy Mondal
Alva Rani James
Santhilal Subhash
Andrew H Sims
Björn Reinius
Eduardo Gorab
Sireesha Uday
Stefan Enroth
Aristidis Moustakas
Journal: Nature Communications (2015)
Discipline: Multidisciplinary
Keywords: lncRNAs; chromatin; gene expression; RNA-DNA triplex; MEG3
Affiliations: Department of Medical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden., Department of Immunology, Genetics and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden., Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, SE-405 30 Gothenburg, Sweden., 1] Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, PO Box 582, SE-751 23 Uppsala, Sweden [2] Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, PO Box 595, SE-751 24 Uppsala, Sweden., Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia BC V5Z 4S6, Canada., Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research UK Centre, Edinburgh EH4 2XR, UK., Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg 412 96, Sweden., Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP:05508-090, Brazil.

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. 

Retracted: No

PubPeer comments:
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