title: MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression.
abstract: 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 × 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.
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Steven W
authors: SW
authors: Paugh
authors: High Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: David R
authors: DR
authors: Coss
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Ju
authors: J
authors: Bao
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Lucas T
authors: LT
authors: Laudermilk
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Christy R
authors: CR
authors: Grace
authors: High Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Antonio M
authors: AM
authors: Ferreira
authors: Molecular Interaction Analysis Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: M Brett
authors: MB
authors: Waddell
authors: Functional Genomics Laboratory, Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Granger
authors: G
authors: Ridout
authors: Functional Genomics Laboratory, Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Deanna
authors: D
authors: Naeve
authors: Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America.
authors: Michael
authors: M
authors: Leuze
authors: Doctoral Training Centre, University of Oxford, Oxford, United Kingdom.
authors: Philip F
authors: PF
authors: LoCascio
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: John C
authors: JC
authors: Panetta
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Mark R
authors: MR
authors: Wilkinson
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Department of Information Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Clayton W
authors: CW
authors: Naeve
authors: Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America.
authors: Edward C
authors: EC
authors: Uberbacher
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Erik J
authors: EJ
authors: Bonten
authors: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: William E
authors: WE
authors: Evans
mesh_terms: D000465:Algorithms; D001482:Base Composition / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C051802:triplex DNA; D004247:DNA