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

Journal article
Authors 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
Published in Nature Communications
Volume 6
Pages art no. 7743
ISSN 2041-1723
Publication year 2015
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages art no. 7743
Language en
Links dx.doi.org/10.1038/ncomms8743
https://gup.ub.gu.se/file/172114
Keywords 'Long non coding RNAs', 'MEG3', 'noncoding'
Subject categories Molecular biology, Medical Engineering, Basic Medicine, Medical Biotechnology

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.

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