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A wide-spread, yet not validated, assumption is that the targetome of miRNAs is non-randomly distributed across the transcriptome and that targets share functional pathways. We developed a computational and experimental strategy termed high-throughput miRNA interaction reporter assay (HiTmIR) to facilitate the validation of target pathways. First, targets and target pathways are predicted and prioritized by computational means to increase the specificity and positive predictive value. Second, the novel webtool miRTaH facilitates guided designs of reporter assay constructs at scale. Third, automated and standardized reporter assays are performed. We evaluated HiTmIR using miR-34a-5p, for which TNF- and TGFB-signaling, and Parkinson's Disease (PD)-related categories were identified and repeated the pipeline for miR-7-5p. HiTmIR validated 58.9% of the target genes for miR-34a-5p and 46.7% for miR-7-5p. We confirmed the targeting by measuring the endogenous protein levels of targets in a neuronal cell model. The standardized positive and negative targets are collected in the new miRATBase database, representing a resource for training, or benchmarking new target predictors. Applied to 88 target predictors with different confidence scores, TargetScan 7.2 and miRanda outperformed other tools. Our experiments demonstrate the efficiency of HiTmIR and provide evidence for an orchestrated miRNA-gene targeting.<\/jats:p>","DOI":"10.1093\/nar\/gkaa1161","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T15:12:22Z","timestamp":1605280342000},"page":"127-144","source":"Crossref","is-referenced-by-count":69,"title":["Validation of human microRNA target pathways enables evaluation of target prediction tools"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8223-3750","authenticated-orcid":false,"given":"Fabian","family":"Kern","sequence":"first","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Krammes","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Danz","sequence":"additional","affiliation":[{"name":"Department of Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering, 66280 Sulzbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3222-8419","authenticated-orcid":false,"given":"Caroline","family":"Diener","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9523-7566","authenticated-orcid":false,"given":"Tim","family":"Kehl","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics, Saarland Informatics Campus, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"K\u00fcchler","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1967-2918","authenticated-orcid":false,"given":"Tobias","family":"Fehlmann","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5536-048X","authenticated-orcid":false,"given":"Mustafa","family":"Kahraman","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Rheinheimer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Aparicio-Puerta","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"},{"name":"Department of Genetics, Faculty of Science, University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs. Granada, University of Granada, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering, 66280 Sulzbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-7567","authenticated-orcid":false,"given":"Nicole","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"},{"name":"Center of Human and Molecular Biology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9330-9290","authenticated-orcid":false,"given":"Christina","family":"Backes","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-9961","authenticated-orcid":false,"given":"Hans-Peter","family":"Lenhof","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics, Saarland Informatics Campus, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-4226","authenticated-orcid":false,"given":"Hagen","family":"von\u00a0Briesen","sequence":"additional","affiliation":[{"name":"Department of Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering, 66280 Sulzbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9361-8106","authenticated-orcid":false,"given":"Martin","family":"Hart","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5361-0895","authenticated-orcid":false,"given":"Andreas","family":"Keller","sequence":"additional","affiliation":[{"name":"Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"},{"name":"Center for Bioinformatics, Saarland Informatics Campus, Saarland University, 66123 Saarbr\u00fccken, Germany"},{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7569-819X","authenticated-orcid":false,"given":"Eckart","family":"Meese","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,10]]},"reference":[{"key":"2021011005244722500_B1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1261\/rna.2183803","article-title":"A uniform system for microRNA annotation","volume":"9","author":"Ambros","year":"2003","journal-title":"RNA"},{"key":"2021011005244722500_B2","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.1038\/sj.onc.1209909","article-title":"Principles and effects of microRNA-mediated post-transcriptional gene regulation","volume":"25","author":"Engels","year":"2006","journal-title":"Oncogene"},{"key":"2021011005244722500_B3","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1261\/rna.2384610","article-title":"Mechanism of translational regulation by miR-2 from sites in the 5\u2032 untranslated region or the open reading frame","volume":"16","author":"Moretti","year":"2010","journal-title":"RNA"},{"key":"2021011005244722500_B4","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nmeth.1682","article-title":"Toward the blood-borne miRNome of human diseases","volume":"8","author":"Keller","year":"2011","journal-title":"Nat. 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