starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data

Abstract Although microRNAs (miRNAs), other non-coding RNAs (ncRNAs) (e.g. lncRNAs, pseudogenes and circRNAs) and competing endogenous RNAs (ceRNAs) have been implicated in cell-fate determination and in various human diseases, surprisingly little is known about the regulatory interaction networks among the multiple classes of RNAs. In this study, we developed starBase v2.0 (http://starbase.sysu.edu.cn/) to systematically identify the RNA–RNA and protein–RNA interaction networks from 108 CLIP-Seq (PAR-CLIP, HITS-CLIP, iCLIP, CLASH) data sets generated by 37 independent studies. By analyzing millions of RNA-binding protein binding sites, we identified ∼9000 miRNA-circRNA, 16 000 miRNA-pseudogene and 285 000 protein–RNA regulatory relationships. Moreover, starBase v2.0 has been updated to provide the most comprehensive CLIP-Seq experimentally supported miRNA-mRNA and miRNA-lncRNA interaction networks to date. We identified ∼10 000 ceRNA pairs from CLIP-supported miRNA target sites. By combining 13 functional genomic annotations, we developed miRFunction and ceRNAFunction web servers to predict the function of miRNAs and other ncRNAs from the miRNA-mediated regulatory networks. Finally, we developed interactive web implementations to provide visualization, analysis and downloading of the aforementioned large-scale data sets. This study will greatly expand our understanding of ncRNA functions and their coordinated regulatory networks.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  Ana Kozomara,et al.  miRBase: integrating microRNA annotation and deep-sequencing data , 2010, Nucleic Acids Res..

[3]  Deeksha Bhartiya,et al.  Systematic Transcriptome Wide Analysis of lncRNA-miRNA Interactions , 2012, PloS one.

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

[5]  Hiroaki Kitano,et al.  The PANTHER database of protein families, subfamilies, functions and pathways , 2004, Nucleic Acids Res..

[6]  M. Todesco,et al.  Target mimicry provides a new mechanism for regulation of microRNA activity , 2007, Nature Genetics.

[7]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[8]  Aaron R. Quinlan,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2022 .

[9]  Anjali J. Koppal,et al.  Supplementary data: Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites , 2010 .

[10]  J. Ule,et al.  Protein–RNA interactions: new genomic technologies and perspectives , 2012, Nature Reviews Genetics.

[11]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[12]  Julian König,et al.  Protein–RNA interactions: new genomic technologies and perspectives , 2012, Nature Reviews Genetics.

[13]  Ting Wang,et al.  The UCSC Genome Browser Database: update 2009 , 2008, Nucleic Acids Res..

[14]  Leszek Rychlewski,et al.  FFAS03: a server for profile–profile sequence alignments , 2005, Nucleic Acids Res..

[15]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[16]  J. Kjems,et al.  Natural RNA circles function as efficient microRNA sponges , 2013, Nature.

[17]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[18]  P. Pandolfi,et al.  A coding-independent function of gene and pseudogene mRNAs regulates tumour biology , 2010, Nature.

[19]  Thomas Tuschl,et al.  Identification of RNA–protein interaction networks using PAR‐CLIP , 2012, Wiley interdisciplinary reviews. RNA.

[20]  Christoph Dieterich,et al.  doRiNA: a database of RNA interactions in post-transcriptional regulation , 2011, Nucleic Acids Res..

[21]  Lincoln Stein,et al.  Reactome knowledgebase of human biological pathways and processes , 2008, Nucleic Acids Res..

[22]  Wonshik Han,et al.  NFIB is a potential target for estrogen receptor‐negative breast cancers , 2011, Molecular oncology.

[23]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

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

[25]  Chi-Ying F. Huang,et al.  miRTarBase: a database curates experimentally validated microRNA–target interactions , 2010, Nucleic Acids Res..

[26]  Mohsen Khorshid,et al.  CLIPZ: a database and analysis environment for experimentally determined binding sites of RNA-binding proteins , 2010, Nucleic Acids Res..

[27]  C. Norbury,et al.  The Long and Short of MicroRNA , 2013, Cell.

[28]  Martin Reczko,et al.  DIANA-LncBase: experimentally verified and computationally predicted microRNA targets on long non-coding RNAs , 2012, Nucleic Acids Res..

[29]  Uwe Ohler,et al.  PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data , 2011, Genome Biology.

[30]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[31]  Howard Y. Chang,et al.  Long Noncoding RNAs: Cellular Address Codes in Development and Disease , 2013, Cell.

[32]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[33]  Helga Thorvaldsdóttir,et al.  Molecular signatures database (MSigDB) 3.0 , 2011, Bioinform..

[34]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[35]  C. Riling,et al.  TGF-β induces the expression of Nedd4 family-interacting protein 1 (Ndfip1) to silence IL-4 production during iTreg cell differentiation , 2011, Nature Immunology.

[36]  Levi Garraway,et al.  Nuclear factor I/B is an oncogene in small cell lung cancer. , 2011, Genes & development.

[37]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2011 , 2011, Nucleic Acids Res..

[38]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[39]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[40]  Ferdinando Di Cunto,et al.  Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs , 2011, Cell.

[41]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[42]  P. Pandolfi,et al.  In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma , 2011, Cell.

[43]  Robert B Darnell,et al.  HITS‐CLIP: panoramic views of protein–RNA regulation in living cells , 2010, Wiley interdisciplinary reviews. RNA.

[44]  Andrew M. Jenkinson,et al.  Ensembl 2009 , 2008, Nucleic Acids Res..

[45]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[46]  Ke Liu,et al.  Linc2GO: a human LincRNA function annotation resource based on ceRNA hypothesis , 2013, Bioinform..

[47]  Sebastian D. Mackowiak,et al.  Circular RNAs are a large class of animal RNAs with regulatory potency , 2013, Nature.

[48]  Hui Zhou,et al.  starBase: a database for exploring microRNA–mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data , 2010, Nucleic Acids Res..

[49]  Xuerui Yang,et al.  An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma , 2011, Cell.