Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 12, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1004744
Keywords
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Funding
- NIH National Cancer Institute [R37 CA36401]
- NIH National Institute of General Medical Sciences Pharmacogenomics Research Network [U01 GM92666, P50 GM115279]
- NIH [F32 CA141762]
- Cancer Center from the National Cancer Institute [CA 21765]
- St. Jude Rhodes College Summer Plus Program
- American Lebanese Syrian Associated Charities (ALSAC)
- Oak Ridge National Laboratory [DE-AC05-00OR22725]
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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 purinerich 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 x 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.
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