%0 Journal Article
%T MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression
%A Steven W. Paugh&nbsp
%A David R. Coss&nbsp
%A Ju Bao&nbsp
%A Lucas T. Laudermilk&nbsp
%A Christy R. Grace&nbsp
%A Antonio M. Ferreira&nbsp
%A M. Brett Waddell&nbsp
%A Granger Ridout&nbsp
%A Deanna Naeve&nbsp
%A Michael Leuze
%J PLOS Computational Biology
%D 2016
%I Public Library of Science (PLoS)
%R 10.1371/journal.pcbi.1004744
%X MicroRNAs are important regulators of gene expression, acting primarily by binding to sequence-specific locations on already transcribed messenger RNAs (mRNA) and typically down-regulating their stability or translation. Recent studies indicate that microRNAs may also play a role in up-regulating mRNA transcription levels, although a definitive mechanism has not been established. Double-helical DNA is capable of forming triple-helical structures through Hoogsteen and reverse Hoogsteen interactions in the major groove of the duplex, and we show physical evidence (i.e., NMR, FRET, SPR) that purine or pyrimidine-rich microRNAs of appropriate length and sequence form triple-helical structures with purine-rich sequences of duplex DNA, and identify microRNA sequences that favor triplex formation. We developed an algorithm (Trident) to search genome-wide for potential triplex-forming sites and show that several mammalian and non-mammalian genomes are enriched for strong microRNA triplex binding sites. We show that those genes containing sequences favoring microRNA triplex formation are markedly enriched (3.3 fold, p<2.2 ¡Á 10£¿16) for genes whose expression is positively correlated with expression of microRNAs targeting triplex binding sequences. This work has thus revealed a new mechanism by which microRNAs could interact with gene promoter regions to modify gene transcription.
%U http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004744