{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T01:07:43Z","timestamp":1780362463317,"version":"3.54.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T00:00:00Z","timestamp":1564704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 MH117122"],"award-info":[{"award-number":["R01 MH117122"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006528","name":"Emory Alzheimer\u2019s Disease Research Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006528","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>Circular RNAs (circRNAs), a class of non-coding RNAs generated from non-canonical back-splicing events, have emerged to play key roles in many biological processes. Though numerous tools have been developed to detect circRNAs from rRNA-depleted RNA-seq data based on back-splicing junction-spanning reads, computational tools to identify critical genomic features regulating circRNA biogenesis are still lacking. In addition, rigorous statistical methods to perform differential expression (DE) analysis of circRNAs remain under-developed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We present circMeta, a unified computational framework for circRNA analyses. circMeta has three primary functional modules: (i) a pipeline for comprehensive genomic feature annotation related to circRNA biogenesis, including length of introns flanking circularized exons, repetitive elements such as Alu elements and SINEs, competition score for forming circulation and RNA editing in back-splicing flanking introns; (ii) a two-stage DE approach of circRNAs based on circular junction reads to quantitatively compare circRNA levels and (iii) a Bayesian hierarchical model for DE analysis of circRNAs based on the ratio of circular reads to linear reads in back-splicing sites to study spatial and temporal regulation of circRNA production. Both proposed DE methods without and with considering host genes outperform existing methods by obtaining better control of false discovery rate and comparable statistical power. Moreover, the identified DE circRNAs by the proposed two-stage DE approach display potential biological functions in Gene Ontology and circRNA-miRNA\u2013mRNA networks that are not able to be detected using existing mRNA DE methods. Furthermore, top DE circRNAs have been further validated by RT-qPCR using divergent primers spanning back-splicing junctions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>The software circMeta is freely available at https:\/\/github.com\/lichen-lab\/circMeta.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz606","type":"journal-article","created":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T03:10:30Z","timestamp":1564629030000},"page":"539-545","source":"Crossref","is-referenced-by-count":26,"title":["circMeta: a unified computational framework for genomic feature annotation and differential expression analysis of circular RNAs"],"prefix":"10.1093","volume":"36","author":[{"given":"Li","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Health Outcomes Research and Policy , Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C","family":"Bruggeman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Health Outcomes Research and Policy , Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,2]]},"reference":[{"key":"2023013112084698400_btz606-B1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Series B Methodol"},{"key":"2023013112084698400_btz606-B2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nrm.2015.32","article-title":"The biogenesis and emerging roles of circular RNAs","volume":"17","author":"Chen","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"2023013112084698400_btz606-B3","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cell.2019.01.025","article-title":"Widespread and functional RNA circularization in localized prostate cancer","volume":"176","author":"Chen","year":"2019","journal-title":"Cell"},{"key":"2023013112084698400_btz606-B4","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/bioinformatics\/btv656","article-title":"Specific identification and quantification of circular RNAs from sequencing data","volume":"32","author":"Cheng","year":"2016","journal-title":"Bioinformatics"},{"key":"2023013112084698400_btz606-B5","doi-asserted-by":"crossref","first-page":"e69.","DOI":"10.1093\/nar\/gku154","article-title":"A Bayesian hierarchical model to detect differentially methylated loci from single nucleotide resolution sequencing data","volume":"42","author":"Feng","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B6","doi-asserted-by":"crossref","first-page":"4.","DOI":"10.1186\/s13059-014-0571-3","article-title":"CIRI: an efficient and unbiased algorithm for de novo circular RNA identification","volume":"16","author":"Gao","year":"2015","journal-title":"Genome Biol"},{"key":"2023013112084698400_btz606-B7","doi-asserted-by":"crossref","first-page":"e58.","DOI":"10.1093\/nar\/gkv1458","article-title":"Comparison of circular RNA prediction tools","volume":"44","author":"Hansen","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B8","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.neuro.24.1.677","article-title":"Neurotrophins: roles in neuronal development and function","volume":"24","author":"Huang","year":"2001","journal-title":"Annu. Rev. Neurosci"},{"key":"2023013112084698400_btz606-B9","doi-asserted-by":"crossref","first-page":"R36.","DOI":"10.1186\/gb-2013-14-4-r36","article-title":"TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions","volume":"14","author":"Kim","year":"2013","journal-title":"Genome Biol"},{"key":"2023013112084698400_btz606-B10","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1093\/bioinformatics\/btq285","article-title":"DARNED: a database of RNA editing in humans","volume":"26","author":"Kiran","year":"2010","journal-title":"Bioinformatics"},{"key":"2023013112084698400_btz606-B11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13040-014-0034-0","article-title":"Performance of genetic programming optimised Bowtie2 on genome comparison and analytic testing (GCAT) benchmarks","volume":"8","author":"Langdon","year":"2015","journal-title":"BioData Min"},{"key":"2023013112084698400_btz606-B12","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013112084698400_btz606-B13","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013112084698400_btz606-B14","doi-asserted-by":"crossref","first-page":"D92","DOI":"10.1093\/nar\/gkt1248","article-title":"starBase v2.0: decoding miRNA\u2013ceRNA, miRNA\u2013ncRNA and protein\u2013RNA interaction networks from large-scale clip-seq data","volume":"42","author":"Li","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B15","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.molcel.2018.06.034","article-title":"The biogenesis, functions, and challenges of circular RNAs","volume":"71","author":"Li","year":"2018","journal-title":"Mol. Cell"},{"key":"2023013112084698400_btz606-B16","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.molcel.2017.10.034","article-title":"The output of protein-coding genes shifts to circular RNAs when the pre-mRNA processing machinery is limiting","volume":"68","author":"Liang","year":"2017","journal-title":"Mol. Cell"},{"key":"2023013112084698400_btz606-B17","doi-asserted-by":"crossref","first-page":"550.","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2023013112084698400_btz606-B18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature11928","article-title":"Circular RNAs are a large class of animal RNAs with regulatory potency","volume":"495","author":"Memczak","year":"2013","journal-title":"Nature"},{"key":"2023013112084698400_btz606-B19","doi-asserted-by":"crossref","first-page":"8168","DOI":"10.1093\/nar\/gky721","article-title":"Circular RNA expression in human hematopoietic cells is widespread and cell-type specific","volume":"46","author":"Nicolet","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B20","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/0092-8674(91)90244-S","article-title":"Scrambled exons","volume":"64","author":"Nigro","year":"1991","journal-title":"Cell"},{"key":"2023013112084698400_btz606-B21","doi-asserted-by":"crossref","first-page":"eaam8526.","DOI":"10.1126\/science.aam8526","article-title":"Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function","volume":"357","author":"Piwecka","year":"2017","journal-title":"Science"},{"key":"2023013112084698400_btz606-B22","doi-asserted-by":"crossref","first-page":"D109","DOI":"10.1093\/nar\/gkt996","article-title":"RADAR: a rigorously annotated database of A-to-I RNA editing","volume":"42","author":"Ramaswami","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"2023013112084698400_btz606-B24","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.molcel.2015.03.027","article-title":"Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed","volume":"58","author":"Rybak-Wolf","year":"2015","journal-title":"Mol. Cell"},{"key":"2023013112084698400_btz606-B25","doi-asserted-by":"crossref","first-page":"e1003777.","DOI":"10.1371\/journal.pgen.1003777","article-title":"Cell-type specific features of circular RNA expression","volume":"9","author":"Salzman","year":"2013","journal-title":"PLoS Genet"},{"key":"2023013112084698400_btz606-B26","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/nprot.2015.037","article-title":"Transcriptome-wide identification of adenosine-to-inosine editing using the ice-seq method","volume":"10","author":"Suzuki","year":"2015","journal-title":"Nat. Protoc"},{"key":"2023013112084698400_btz606-B27","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nrg.2016.114","article-title":"Detecting circular RNAs: bioinformatic and experimental challenges","volume":"17","author":"Szabo","year":"2016","journal-title":"Nat. Rev. Genet"},{"key":"2023013112084698400_btz606-B28","doi-asserted-by":"crossref","first-page":"D663.","DOI":"10.1093\/nar\/gkl1017","article-title":"The ENCODE project at UC Santa Cruz","volume":"35","author":"Thomas","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B29","doi-asserted-by":"crossref","first-page":"W460","DOI":"10.1093\/nar\/gkv403","article-title":"DIANA-miRPath v3.0: deciphering microRNA function with experimental support","volume":"43","author":"Vlachos","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B30","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.cell.2018.12.021","article-title":"The landscape of circular RNA in cancer","volume":"176","author":"Vo","year":"2019","journal-title":"Cell"},{"key":"2023013112084698400_btz606-B31","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1016\/j.celrep.2014.10.062","article-title":"Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation","volume":"9","author":"Westholm","year":"2014","journal-title":"Cell Rep"},{"key":"2023013112084698400_btz606-B32","doi-asserted-by":"crossref","first-page":"e1478.","DOI":"10.1002\/wrna.1478","article-title":"A 360 degrees view of circular RNAs: from biogenesis to functions","volume":"9","author":"Wilusz","year":"2018","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"2023013112084698400_btz606-B33","doi-asserted-by":"crossref","first-page":"D202","DOI":"10.1093\/nar\/gkq1056","article-title":"starBase: a database for exploring microRNA\u2013mRNA interaction maps from Argonaute clip-seq and degradome-seq data","volume":"39","author":"Yang","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2023013112084698400_btz606-B34","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cell.2014.09.001","article-title":"Complementary sequence-mediated exon circularization","volume":"159","author":"Zhang","year":"2014","journal-title":"Cell"},{"key":"2023013112084698400_btz606-B35","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1016\/j.celrep.2017.08.027","article-title":"Genome-wide maps of m6a circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs","volume":"20","author":"Zhou","year":"2017","journal-title":"Cell Rep"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz606\/29965818\/btz606.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/2\/539\/48991802\/btz606.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/2\/539\/48991802\/btz606.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,21]],"date-time":"2024-07-21T15:38:12Z","timestamp":1721576292000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/2\/539\/5543088"}},"subtitle":[],"editor":[{"given":"Arne","family":"Elofsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2019,8,2]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,1,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz606","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,1,15]]},"published":{"date-parts":[[2019,8,2]]}}}