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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.

SUBMITTER: Paugh SW

PROVIDER: S-EPMC4742280 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression.

Paugh Steven W SW Coss David R DR Bao Ju J Laudermilk Lucas T LT Grace Christy R CR Ferreira Antonio M AM Waddell M Brett MB Ridout Granger G Naeve Deanna D Leuze Michael M LoCascio Philip F PF Panetta John C JC Wilkinson Mark R MR Pui Ching-Hon CH Naeve Clayton W CW Uberbacher Edward C EC Bonten Erik J EJ Evans William E WE

PLoS computational biology 20160204 2

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 interactio ...[more]

PMID: 26844769

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Project description:Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of COPD patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and NK cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative data sets, gene sets defined by poly I:C-induced DEGs were enriched in the molecular profiles of chronic obstructive pulmonary disease (COPD), but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients. Temporal genomic characterization of lung homogenate from male BALB/cJ mice treated intranasally with poly I:C or saline was carried out at 7 timepoints post poly I:C/saline adiministration (2, 6, 24, 48, 72, 96, 168 hours). Mice were anesthetized with isoflurane and intranasally (i.n.) administered saline or poly I:C (InvivoGen, San Diego, CA) at a sub-maximal dose of 30 µg in 50 µl sterile saline. For time course studies, the 30 µg was administered i.n. once and assessed from 2 – 168 hours. Total RNA was isolated from the mouse lung tissue of poly I:C and saline treated mice across 7 time points (2, 6, 24, 48, 72, 96, and 168 hours, n=6 per group) and homogenized in QIAzol reagent. Purified total RNA was amplified and labeled using NuGen Ovation kits (NuGEN Technologies, Inc., San Carlos, CA) and RNA from samples was hybridized to Affymetrix Mouse 430 2.0 arrays.

Dataset Information

MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression.

Publications

MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression.

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