Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
Tóm tắt
System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement.
Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios.
Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at:
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Tài liệu tham khảo
Huang DW, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009, 37: 1-13. 10.1093/nar/gkn923.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005, 102: 15545-15550. 10.1073/pnas.0506580102.
Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP: GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007, 23: 3251-3253. 10.1093/bioinformatics/btm369.
Smirnov N: Tables for estimating the goodness of fit of empirical distributions. Ann Math Stat. 1948, 19: 279-281. 10.1214/aoms/1177730256.
Liberzon A, Subramanian A, Pinchback R, Thorvaldsdóttir H, Tamayo P: Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011, 27: 1739-1740. 10.1093/bioinformatics/btr260.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H: Gene ontology: tool for the unification of biology. Nat Genet. 2000, 25: 25-10.1038/75556.
Fisher RA: On the interpretation of χ2 from contingency tables, and the calculation of P. J R Stat Soc. 1922, 85: 87-94. 10.2307/2340521.
Dannenfelser R, Clark N, Ma'ayan A: Genes2FANs: connecting genes through functional association networks. BMC Bioinforma. 2012, 13: 156-10.1186/1471-2105-13-156.
Clark N, Dannenfelser R, Tan C, Komosinski M, Ma'ayan A: Sets2Networks: network inference from repeated observations of sets. BMC Syst Biol. 2012, 6: 89-10.1186/1752-0509-6-89.
Lachmann A, Xu H, Krishnan J, Berger SI, Mazloom AR: ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics. 2010, 26: 2438-2444. 10.1093/bioinformatics/btq466.
Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S: TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2006, 34: D108-D110. 10.1093/nar/gkj143.
Portales-Casamar E, Thongjuea S, Kwon AT, Arenillas D, Zhao X: JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Res. 2010, 38: D105-D110. 10.1093/nar/gkp950.
Kuhn RM, Karolchik D, Zweig AS, Trumbower H, Thomas DJ: The UCSC genome browser database: update 2007. Nucleic Acids Res. 2007, 35: D668-D673. 10.1093/nar/gkl928.
Rosenbloom KR, Dreszer TR, Long JC, Malladi VS, Sloan CA: ENCODE whole-genome data in the UCSC Genome Browser: update 2012. Nucleic Acids Res. 2012, 40: D912-D917. 10.1093/nar/gkr1012.
Consortium TEP: An integrated encyclopedia of DNA elements in the human genome. Nature. 2012, 489: 57-74. 10.1038/nature11247.
Chadwick LH: The NIH roadmap epigenomics program data resource. Epigenomics. 2012, 4: 317-324. 10.2217/epi.12.18.
Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are MicroRNA targets. Cell. 2005, 120: 15-20. 10.1016/j.cell.2004.12.035.
Chen EY, Xu H, Gordonov S, Lim MP, Perkins MH: Expression2Kinases: mRNA profiling linked to multiple upstream regulatory layers. Bioinformatics. 2012, 28: 105-111. 10.1093/bioinformatics/btr625.
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS: Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008, 9: R137-10.1186/gb-2008-9-9-r137.
Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A: The NIH roadmap epigenomics mapping consortium. Nat Biotechnol. 2010, 28: 1045-1048. 10.1038/nbt1010-1045.
Zang C, Schones DE, Zeng C, Cui K, Zhao K: A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics. 2009, 25: 1952-1958. 10.1093/bioinformatics/btp340.
Pepke S, Wold B, Mortazavi A: Computation for ChIP-seq and RNA-seq studies. Nat Methods. 2009, 6: S22-S32. 10.1038/nmeth.1371.
Lewis BP, Shih I, Jones-Rhoades MW, Bartel DP, Burge CB: Prediction of mammalian microRNA targets. Cell. 2003, 115: 787-798. 10.1016/S0092-8674(03)01018-3.
Lachmann A, Ma'ayan A: Lists2Networks: integrated analysis of gene/protein lists. BMC Bioinforma. 2010, 11: 87-10.1186/1471-2105-11-87.
Pico AR, Kelder T, Van Iersel MP, Hanspers K, Conklin BR: WikiPathways: pathway editing for the people. PLoS Biol. 2008, 6: e184-10.1371/journal.pbio.0060184.
Ogata H, Goto S, Fujibuchi W, Kanehisa M: Computation with the KEGG pathway database. Biosystems. 1998, 47: 119-128. 10.1016/S0303-2647(98)00017-3.
Joshi-Tope G, Gillespie M, Vastrik I, D'Eustachio P, Schmidt E: Reactome: a knowledgebase of biological pathways. Nucleic Acids Res. 2005, 33: D428-D432.
Lachmann A, Ma'ayan A: KEA: kinase enrichment analysis. Bioinformatics. 2009, 25: 684-686. 10.1093/bioinformatics/btp026.
Ruepp A, Brauner B, Dunger-Kaltenbach I, Frishman G, Montrone C: CORUM: the comprehensive resource of mammalian protein complexes. Nucleic Acids Res. 2008, 36: D646-D650.
Malovannaya A, Lanz RB, Jung SY, Bulynko Y, Le NT: Analysis of the human endogenous coregulator complexome. Cell. 2011, 145: 787-799. 10.1016/j.cell.2011.05.006.
Graauw M, Pimienta G, Chaerkady R, Pandey A: SILAC for Global Phosphoproteomic Analysis. 2009, Phospho-Proteomics: Humana Press, 107-116.
Prasad TSK, Goel R, Kandasamy K, Keerthikumar S, Kumar S: Human protein reference database—2009 update. Nucleic Acids Res. 2009, 37: D767-D772. 10.1093/nar/gkn892.
Hornbeck PV, Chabra I, Kornhauser JM, Skrzypek E, Zhang B: PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics. 2004, 4: 1551-1561. 10.1002/pmic.200300772.
Yang CY, Chang CH, Yu YL, Lin TCE, Lee SA: PhosphoPOINT: a comprehensive human kinase interactome and phospho-protein database. Bioinformatics. 2008, 24: i14-i20. 10.1093/bioinformatics/btn297.
Diella F, Cameron S, Gemünd C, Linding R, Via A: Phospho. ELM: a database of experimentally verified phosphorylation sites in eukaryotic proteins. BMC Bioinforma. 2004, 5: 79-10.1186/1471-2105-5-79.
Linding R, Jensen LJ, Pasculescu A, Olhovsky M, Colwill K: NetworKIN: a resource for exploring cellular phosphorylation networks. Nucleic Acids Res. 2008, 36: D695-D699.
Zanzoni A, Montecchi-Palazzi L, Quondam M, Ausiello G, Helmer-Citterich M: MINT: a Molecular INTeraction database. FEBS Lett. 2002, 513: 135-140. 10.1016/S0014-5793(01)03293-8.
Blake JA, Bult CJ, Eppig JT, Kadin JA, Richardson JE: The mouse genome database genotypes: phenotypes. Nucleic Acids Res. 2009, 37: D712-D719. 10.1093/nar/gkn886.
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC: The connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science Signalling. 2006, 313: 1929-
Culhane AC, Schwarzl T, Sultana R, Picard KC, Picard SC: GeneSigDB—a curated database of gene expression signatures. Nucleic Acids Res. 2010, 38: D716-D725. 10.1093/nar/gkp1015.
Hamosh A, Scott AF, Amberger J, Valle D, McKusick VA: Online Mendelian inheritance in man (OMIM). Hum Mutat. 1999, 15: 57-61.
Chatr-aryamontri A, Ceol A, Peluso D, Nardozza A, Panni S: VirusMINT: a viral protein interaction database. Nucleic Acids Res. 2009, 37: D669-D673. 10.1093/nar/gkn739.
Berger SI, Posner JM, Ma'ayan A: Genes2Networks: connecting lists of gene symbols using mammalian protein interactions databases. BMC Bioinforma. 2007, 8: 372-10.1186/1471-2105-8-372.
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA: A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004, 101: 6062-6067. 10.1073/pnas.0400782101.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA: The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012, 483: 603-607. 10.1038/nature11003.
Weinstein JN: Spotlight on molecular profiling:“integromic†analysis of the NCI-60 cancer cell lines. Mol Cancer Ther. 2006, 5: 2601-2605. 10.1158/1535-7163.MCT-06-0640.
Wishart DS, Tzur D, Knox C, Eisner R, Guo AC: HMDB: the human metabolome database. Nucleic Acids Res. 2007, 35: D521-D526. 10.1093/nar/gkl923.
Bateman A, Coin L, Durbin R, Finn RD, Hollich V: The Pfam protein families database. Nucleic Acids Res. 2004, 32: D138-D141. 10.1093/nar/gkh121.
Apweiler R, Attwood TK, Bairoch A, Birney E, Biswas M: The InterPro database, an integrated documentation resource for protein families, domains and functional sites. Nucleic Acids Res. 2001, 29: 37-40. 10.1093/nar/29.1.37.
Skellam J: Studies in statistical ecology: I Spatial pattern. Biometrika. 1952, 39: 346-362.
Clark PJ, Evans FC: Distance to nearest neighbor as a measure of spatial relationships in populations. Ecology. 1954, 35: 445-453. 10.2307/1931034.
Bostock M, Ogievetsky V, Heer J: D3 Data-Driven Documents. IEEE T Vis Comput Gr. 2011, 17: 2301-2309.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G: Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotech. 2010, 28: 511-515. 10.1038/nbt.1621.