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

By T. Mondal, Santhilal Subhash, Roshan Vaid, Stefan Enroth, S. Uday, Björn Reinius, Sanhita Mitra, A. Mohammed, A. R. James, E. Hoberg and 8 more. Nature Communications, 2015

636 citations recorded by the source corpus.

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. Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin. Here, the authors show that lncRNA MEG3regulates the TGF-β pathway by bridging the interactions between polycomb repressive complex 2 and the distal regulatory elements of the TGF-β pathway genes via formation of RNA–DNA triplexes.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eb7646434273d8e4eddc6442e664449e4a780554

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Citations in the corpus

TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis (2019, neutral): “MEG3 [134,153,154] Regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures, and downregulates AKT and functions as a sponge of miR-421 to regulate E-cadherin expression.”
Mechanisms of long noncoding RNA function in development and disease (2016, background): “Gtl2 (MEG3) LincRNA RTL1 Nucleus Histone modification, DNA methylation Imprinting [55, 122, 177]”
Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, background): “In this way, tapRNA ZF motifs could include the sequestration or delivery of ZF factors to enhancers, for example involving the formation of RNA-DNA hybrids or triplex structures (Mondal et al., 2015; O’Leary et al., 2015).”