Accessibility of microRNA binding sites in metastable RNA secondary structures in the presence of SNPs

MOTIVATION We study microRNA (miRNA) bindings to metastable RNA secondary structures close to minimum free energy conformations in the context of single nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) concentration levels, i.e. whether features of miRNA bindings to metastable conformations could provide additional information supporting the differences in expression levels of the two sequences defined by a SNP. In our study, the instances [mRNA/3'UTR; SNP; miRNA] were selected based on strong expression level analyses, SNP locations within binding regions and the computationally feasible identification of metastable conformations. RESULTS We identified 14 basic cases [mRNA; SNP; miRNA] of 3' UTR-lengths ranging from 124 up to 1078 nt reported in recent literature, and we analyzed the number, structure and miRNA binding to metastable conformations within an energy offset above mfe conformations. For each of the 14 instances, the miRNA binding characteristics are determined by the corresponding STarMir output. Among the different parameters we introduced and analyzed, we found that three of them, related to the average depth and average opening energy of metastable conformations, may provide supporting information for a stronger separation between miRNA bindings to the two alleles defined by a given SNP. AVAILABILITY AND IMPLEMENTATION At http://kks.inf.kcl.ac.uk/MSbind.html the MSbind tool is available for calculating features of metastable conformations determined by putative miRNA binding sites.

[1]  Takaya Saito,et al.  Target gene expression levels and competition between transfected and endogenous microRNAs are strong confounding factors in microRNA high-throughput experiments , 2012, Silence.

[2]  Praveen Sethupathy,et al.  MicroRNA target site polymorphisms and human disease. , 2008, Trends in genetics : TIG.

[3]  Carole Ober,et al.  Allele-specific targeting of microRNAs to HLA-G and risk of asthma. , 2007, American journal of human genetics.

[4]  P. Whorwell,et al.  First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. , 2008, Human molecular genetics.

[5]  Wenbin Ye,et al.  The Effect of Central Loops in miRNA:MRE Duplexes on the Efficiency of miRNA-Mediated Gene Regulation , 2008, PloS one.

[6]  Jan Gorodkin,et al.  RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs , 2013, Human mutation.

[7]  Carla Bosia,et al.  The Role of Incoherent MicroRNA-Mediated Feedforward Loops in Noise Buffering , 2010, PLoS Comput. Biol..

[8]  Mark A. Ragan,et al.  Quantitative Prediction of miRNA-mRNA Interaction Based on Equilibrium Concentrations , 2011, PLoS Comput. Biol..

[9]  C. Lawrence,et al.  RNA secondary structure prediction by centroids in a Boltzmann weighted ensemble. , 2005, RNA.

[10]  T. Nánási,et al.  Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene , 2013, American Journal of Medical Genetics Part B: Neuropsychiatric Genetics.

[11]  Chris Sander,et al.  mRNA turnover rate limits siRNA and microRNA efficacy , 2010, Molecular systems biology.

[12]  W. Guan,et al.  Identification of a New Target of miR-16, Vacuolar Protein Sorting 4a , 2014, PloS one.

[13]  D. Weinberger,et al.  MicroSNiPer: a web tool for prediction of SNP effects on putative microRNA targets , 2010, Human mutation.

[14]  Michal Linial,et al.  Toward a combinatorial nature of microRNA regulation in human cells , 2012, Nucleic acids research.

[15]  I. Jurisica,et al.  NAViGaTing the Micronome – Using Multiple MicroRNA Prediction Databases to Identify Signalling Pathway-Associated MicroRNAs , 2011, PloS one.

[16]  P. Clote,et al.  Computing the Partition Function for Kinetically Trapped RNA Secondary Structures , 2011, PloS one.

[17]  Gaofeng Wang,et al.  Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. , 2008, American journal of human genetics.

[18]  Hanah Margalit,et al.  Competition between small RNAs: a quantitative view. , 2012, Biophysical journal.

[19]  Georg Sczakiel,et al.  MicroRNA-mediated regulation of gene expression is affected by disease-associated SNPs within the 3′-UTR via altered RNA structure , 2012, RNA biology.

[20]  D. Turner,et al.  Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Andrew D. Johnson,et al.  RNA Structures Affected By Single Nucleotide Polymorphisms In Transcribed Regions Of The Human Genome , 2011 .

[22]  Alain Laederach,et al.  Structural effects of linkage disequilibrium on the transcriptome. , 2012, RNA.

[23]  T. Wurdinger,et al.  Cutting Edge: A Variant of the IL-23R Gene Associated with Inflammatory Bowel Disease Induces Loss of MicroRNA Regulation and Enhanced Protein Production , 2012, The Journal of Immunology.

[24]  W. Liu,et al.  A miRNA Binding Site Single-Nucleotide Polymorphism in the 3′-UTR Region of the IL23R Gene Is Associated with Breast Cancer , 2012, PloS one.

[25]  J. Kalabus,et al.  MicroRNAs Differentially Regulate Carbonyl Reductase 1 (CBR1) Gene Expression Dependent on the Allele Status of the Common Polymorphic Variant rs9024 , 2012, PloS one.

[26]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[27]  Yan Cui,et al.  PolymiRTS Database 2.0: linking polymorphisms in microRNA target sites with human diseases and complex traits , 2011, Nucleic Acids Res..

[28]  Michael T. Wolfinger,et al.  Efficient computation of RNA folding dynamics , 2004 .

[29]  Jonathan L Chen,et al.  Testing the Nearest Neighbor Model for Canonical RNA Base Pairs: Revision of GU Parameters , 2012, Biochemistry.

[30]  Anton J. Enright,et al.  MicroRNA targets in Drosophila , 2003, Genome Biology.

[31]  A. Ballabio,et al.  Identification of microRNA-regulated gene networks by expression analysis of target genes , 2012, Genome research.

[32]  C. Sander,et al.  Target mRNA abundance dilutes microRNA and siRNA activity , 2010, Molecular systems biology.

[33]  Ronny Lorenz,et al.  The Vienna RNA Websuite , 2008, Nucleic Acids Res..

[34]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[35]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[36]  Hélène Touzet,et al.  RNA Locally Optimal Secondary Structures , 2012, J. Comput. Biol..

[37]  R. Kulkarni,et al.  Stochastic modeling of regulation of gene expression by multiple small RNAs. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[38]  Hong Guo,et al.  MiR-196a binding-site SNP regulates RAP1A expression contributing to esophageal squamous cell carcinoma risk and metastasis. , 2012, Carcinogenesis.

[39]  Peifang Liu,et al.  Functional SNP in the microRNA-367 binding site in the 3′UTR of the calcium channel ryanodine receptor gene 3 (RYR3) affects breast cancer risk and calcification , 2011, Proceedings of the National Academy of Sciences.

[40]  Andrew E. Bruno,et al.  miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3'UTRs of human genes , 2012, BMC Genomics.

[41]  Erik L. Johnson,et al.  Volatility in mRNA secondary structure as a design principle for antisense , 2012, Nucleic acids research.

[42]  R. Sachidanandam,et al.  High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries , 2012, Nature Methods.

[43]  Q. Cai,et al.  A MicroRNA-7 Binding Site Polymorphism in HOXB5 Leads to Differential Gene Expression in Bladder Cancer , 2012, PloS one.

[44]  Daniel Herschlag,et al.  Multiple Native States Reveal Persistent Ruggedness of an RNA Folding Landscape , 2010, Nature.

[45]  Dang D. Long,et al.  Potent effect of target structure on microRNA function , 2007, Nature Structural &Molecular Biology.

[46]  D. Bartel,et al.  Weak Seed-Pairing Stability and High Target-Site Abundance Decrease the Proficiency of lsy-6 and Other miRNAs , 2011, Nature Structural &Molecular Biology.

[47]  Mario di Bernardo,et al.  Modeling RNA interference in mammalian cells , 2011, BMC Systems Biology.

[48]  F. J. Livesey,et al.  Modelling and measuring single cell RNA expression levels find considerable transcriptional differences among phenotypically identical cells , 2008, BMC Genomics.

[49]  D. Bishop,et al.  The role of microRNA-binding site polymorphisms in DNA repair genes as risk factors for bladder cancer and breast cancer and their impact on radiotherapy outcomes , 2011, Carcinogenesis.

[50]  Peter F. Stadler,et al.  RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs , 2013, Human Mutation.

[51]  Dang D. Long,et al.  mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein–enriched transcripts , 2008, Nature Methods.

[52]  Michael Kertesz,et al.  The role of site accessibility in microRNA target recognition , 2007, Nature Genetics.

[53]  P. Schuster,et al.  Complete suboptimal folding of RNA and the stability of secondary structures. , 1999, Biopolymers.

[54]  Yusuke Nakamura,et al.  ORAI1 Genetic Polymorphisms Associated with the Susceptibility of Atopic Dermatitis in Japanese and Taiwanese Populations , 2012, PloS one.

[55]  Ray M. Marín,et al.  Optimal Use of Conservation and Accessibility Filters in MicroRNA Target Prediction , 2012, PloS one.

[56]  Jianguo Liu,et al.  Grading amino acid properties increased accuracies of single point mutation on protein stability prediction , 2011, BMC Bioinformatics.

[57]  Angel Rubio,et al.  Joint analysis of miRNA and mRNA expression data , 2013, Briefings Bioinform..