{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T13:09:23Z","timestamp":1752671363830,"version":"3.37.3"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KFO311-2","TH903\/20-2","German Academic Exchange Service Graduate School Scholarship Programme (DAAD-GSSP 57320205)"],"award-info":[{"award-number":["KFO311-2","TH903\/20-2","German Academic Exchange Service Graduate School Scholarship Programme (DAAD-GSSP 57320205)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["Era-Net grant 01KT1801","ERA Network grant EXPERT"],"award-info":[{"award-number":["Era-Net grant 01KT1801","ERA Network grant EXPERT"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001652","name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001652","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.<\/jats:p>","DOI":"10.1038\/s41598-021-89531-7","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:03:10Z","timestamp":1623664990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reconstruction of the miR-506-Quaking axis in Idiopathic Pulmonary Fibrosis using integrative multi-source bioinformatics"],"prefix":"10.1038","volume":"11","author":[{"given":"Stevan D.","family":"Stojanovi\u0107","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunguang","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette","family":"Just","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelika","family":"Pfanne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Pich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregor","family":"Warnecke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Braubach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Petzold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danny","family":"Jonigk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg H. W.","family":"Distler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Fiedler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meik","family":"Kunz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"89531_CR1","doi-asserted-by":"publisher","first-page":"4126","DOI":"10.3390\/ijms21114126","volume":"21","author":"SD Stojanovi\u0107","year":"2020","unstructured":"Stojanovi\u0107, S. D. et al. Comprehensive bioinformatics identifies key microRNA players in ATG7-deficient lung fibroblasts. Int. J. Mol. Sci. 21, 4126. https:\/\/doi.org\/10.3390\/ijms21114126 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"89531_CR2","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1056\/NEJMra1705751","volume":"378","author":"DJ Lederer","year":"2018","unstructured":"Lederer, D. J. & Martinez, F. J. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 378, 1811\u20131823. https:\/\/doi.org\/10.1056\/NEJMra1705751 (2018).","journal-title":"N. Engl. J. Med."},{"key":"89531_CR3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12931-019-0977-2","volume":"20","author":"M Zurkova","year":"2019","unstructured":"Zurkova, M. et al. Effect of pirfenidone on lung function decline and survival: 5-yr experience from a real-life IPF cohort from the Czech EMPIRE registry. Respir. Res. 20, 16 (2019).","journal-title":"Respir. Res."},{"key":"89531_CR4","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1016\/s0140-6736(17)30866-8","volume":"389","author":"L Richeldi","year":"2017","unstructured":"Richeldi, L., Collard, H. R. & Jones, M. G. Idiopathic pulmonary fibrosis. Lancet 389, 1941\u20131952. https:\/\/doi.org\/10.1016\/s0140-6736(17)30866-8 (2017).","journal-title":"Lancet"},{"key":"89531_CR5","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1161\/circresaha.117.311335","volume":"122","author":"SK Gupta","year":"2018","unstructured":"Gupta, S. K. et al. Quaking inhibits doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression. Circ. Res. 122, 246\u2013254. https:\/\/doi.org\/10.1161\/circresaha.117.311335 (2018).","journal-title":"Circ. Res."},{"key":"89531_CR6","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1038\/s41586-020-2077-3","volume":"583","author":"EL Van Nostrand","year":"2020","unstructured":"Van Nostrand, E. L. et al. A large-scale binding and functional map of human RNA-binding proteins. Nature 583, 711\u2013719 (2020).","journal-title":"Nature"},{"key":"89531_CR7","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrm.2017.130","volume":"19","author":"MW Hentze","year":"2018","unstructured":"Hentze, M. W., Castello, A., Schwarzl, T. & Preiss, T. A brave new world of RNA-binding proteins. Nat. Rev. Mol. Cell Biol. 19, 327\u2013341. https:\/\/doi.org\/10.1038\/nrm.2017.130 (2018).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"89531_CR8","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1161\/circulationaha.119.039596","volume":"140","author":"S Chothani","year":"2019","unstructured":"Chothani, S. et al. Widespread translational control of fibrosis in the human heart by RNA-binding proteins. Circulation 140, 937\u2013951. https:\/\/doi.org\/10.1161\/circulationaha.119.039596 (2019).","journal-title":"Circulation"},{"key":"89531_CR9","doi-asserted-by":"publisher","first-page":"4727","DOI":"10.3390\/ijms21134727","volume":"21","author":"M Fuchs","year":"2020","unstructured":"Fuchs, M. et al. Integrative bioinformatic analyses of global transcriptome data decipher novel molecular insights into cardiac anti-fibrotic therapies. Int. J. Mol. Sci. 21, 4727. https:\/\/doi.org\/10.3390\/ijms21134727 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"89531_CR10","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41467-020-14349-2","volume":"11","author":"A Foinquinos","year":"2020","unstructured":"Foinquinos, A. et al. Preclinical development of a miR-132 inhibitor for heart failure treatment. Nat. Commun. 11, 633. https:\/\/doi.org\/10.1038\/s41467-020-14349-2 (2020).","journal-title":"Nat. Commun."},{"key":"89531_CR11","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa898","author":"J T\u00e4ubel","year":"2020","unstructured":"T\u00e4ubel, J. et al. Novel antisense therapy targeting microRNA-132 in patients with heart failure: Results of a first-in-human phase 1b randomized, double-blind, placebo-controlled study. Eur. Heart. J. https:\/\/doi.org\/10.1093\/eurheartj\/ehaa898 (2020).","journal-title":"Eur. Heart. J."},{"key":"89531_CR12","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ymeth.2014.11.020","volume":"74","author":"S Pletscher-Frankild","year":"2015","unstructured":"Pletscher-Frankild, S., Pallej\u00e0, A., Tsafou, K., Binder, J. X. & Jensen, L. J. DISEASES: Text mining and data integration of disease\u2013gene associations. Methods 74, 83\u201389. https:\/\/doi.org\/10.1016\/j.ymeth.2014.11.020 (2015).","journal-title":"Methods"},{"key":"89531_CR13","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1136\/thoraxjnl-2013-204596","volume":"70","author":"DJ DePianto","year":"2015","unstructured":"DePianto, D. J. et al. Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax 70, 48\u201356. https:\/\/doi.org\/10.1136\/thoraxjnl-2013-204596 (2015).","journal-title":"Thorax"},{"key":"89531_CR14","doi-asserted-by":"publisher","first-page":"eaba1983","DOI":"10.1126\/sciadv.aba1983","volume":"6","author":"TS Adams","year":"2020","unstructured":"Adams, T. S. et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci. Adv. 6, eaba1983 (2020).","journal-title":"Sci. Adv."},{"key":"89531_CR15","doi-asserted-by":"publisher","first-page":"e05005","DOI":"10.7554\/eLife.05005","volume":"4","author":"V Agarwal","year":"2015","unstructured":"Agarwal, V., Bell, G. W., Nam, J.-W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. Elife 4, e05005. https:\/\/doi.org\/10.7554\/eLife.05005 (2015).","journal-title":"Elife"},{"key":"89531_CR16","doi-asserted-by":"publisher","first-page":"14532","DOI":"10.1038\/ncomms14532","volume":"8","author":"MJ Schafer","year":"2017","unstructured":"Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532. https:\/\/doi.org\/10.1038\/ncomms14532 (2017).","journal-title":"Nat. Commun."},{"key":"89531_CR17","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1093\/eurheartj\/ehz919","volume":"41","author":"SD Stojanovi\u0107","year":"2020","unstructured":"Stojanovi\u0107, S. D., Fiedler, J., Bauersachs, J., Thum, T. & Sedding, D. G. Senescence-induced inflammation: An important player and key therapeutic target in atherosclerosis. Eur. Heart J. 41, 2983\u20132996. https:\/\/doi.org\/10.1093\/eurheartj\/ehz919 (2020).","journal-title":"Eur. Heart J."},{"key":"89531_CR18","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/nature07228","volume":"455","author":"M Selbach","year":"2008","unstructured":"Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58\u201363. https:\/\/doi.org\/10.1038\/nature07228 (2008).","journal-title":"Nature"},{"key":"89531_CR19","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/nature07242","volume":"455","author":"D Baek","year":"2008","unstructured":"Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64\u201371 (2008).","journal-title":"Nature"},{"key":"89531_CR20","doi-asserted-by":"publisher","first-page":"e99016","DOI":"10.15252\/embj.201899016","volume":"37","author":"KA Pillman","year":"2018","unstructured":"Pillman, K. A. et al. miR-200\/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking. EMBO J. 37, e99016. https:\/\/doi.org\/10.15252\/embj.201899016 (2018).","journal-title":"EMBO J."},{"key":"89531_CR21","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1101\/gad.302059.117","volume":"31","author":"WS Fagg","year":"2017","unstructured":"Fagg, W. S. et al. Autogenous cross-regulation of Quaking mRNA processing and translation balances Quaking functions in splicing and translation. Genes Dev. 31, 1894\u20131909. https:\/\/doi.org\/10.1101\/gad.302059.117 (2017).","journal-title":"Genes Dev."},{"key":"89531_CR22","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1183\/13993003.02316-2014","volume":"46","author":"G Raghu","year":"2015","unstructured":"Raghu, G., Amatto, V. C., Behr, J. & Stowasser, S. Comorbidities in idiopathic pulmonary fibrosis patients: A systematic literature review. Eur. Respir. J. 46, 1113\u20131130. https:\/\/doi.org\/10.1183\/13993003.02316-2014 (2015).","journal-title":"Eur. Respir. J."},{"key":"89531_CR23","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.18632\/aging.101877","volume":"11","author":"GJ Wang","year":"2019","unstructured":"Wang, G. J., Jiao, B. P., Liu, Y. J., Li, Y. R. & Deng, B. B. Reactivation of microRNA-506 inhibits gastric carcinoma cell metastasis through ZEB2. Aging 11, 1821\u20131831. https:\/\/doi.org\/10.18632\/aging.101877 (2019).","journal-title":"Aging"},{"key":"89531_CR24","doi-asserted-by":"publisher","first-page":"e49024","DOI":"10.15252\/embr.201949024","volume":"21","author":"Z Wang","year":"2020","unstructured":"Wang, Z. et al. X-linked miR-506 family miRNAs promote FMRP expression in mouse spermatogonia. EMBO Rep. 21, e49024. https:\/\/doi.org\/10.15252\/embr.201949024 (2020).","journal-title":"EMBO Rep."},{"key":"89531_CR25","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550. https:\/\/doi.org\/10.1186\/s13059-014-0550-8 (2014).","journal-title":"Genome Biol."},{"key":"89531_CR26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1021\/acs.jproteome.8b00702","volume":"18","author":"NT Doncheva","year":"2019","unstructured":"Doncheva, N. T., Morris, J. H., Gorodkin, J. & Jensen, L. J. Cytoscape StringApp: Network analysis and visualization of proteomics data. J. Proteome Res. 18, 623\u2013632. https:\/\/doi.org\/10.1021\/acs.jproteome.8b00702 (2019).","journal-title":"J. Proteome Res."},{"key":"89531_CR27","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nmeth.1931","volume":"9","author":"S Orchard","year":"2012","unstructured":"Orchard, S. et al. Protein interaction data curation: The International Molecular Exchange (IMEx) consortium. Nat. Methods 9, 345\u2013350. https:\/\/doi.org\/10.1038\/nmeth.1931 (2012).","journal-title":"Nat. Methods"},{"key":"89531_CR28","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.14613.2","author":"M Kutmon","year":"2019","unstructured":"Kutmon, M., Ehrhart, F., Willighagen, E., Evelo, C. & Coort, S. CyTargetLinker app update: A flexible solution for network extension in Cytoscape [version 2; peer review: 2 approved]. F1000Research https:\/\/doi.org\/10.12688\/f1000research.14613.2 (2019).","journal-title":"F1000Research"},{"issue":"2","key":"89531_CR29","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1093\/bioinformatics\/btm554","volume":"24","author":"Y Assenov","year":"2008","unstructured":"Assenov, Y., Ram\u00edrez, F., Schelhorn, S. E., Lengauer, T., & Albrecht, M. Computing topological parameters of biological networks. Bioinformatics, 24(2), 282\u2013284. https:\/\/doi.org\/10.1093\/bioinformatics\/btm554 (2008).","journal-title":"Bioinformatics"},{"key":"89531_CR30","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","volume":"177","author":"T Stuart","year":"2019","unstructured":"Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888-1902.e1821. https:\/\/doi.org\/10.1016\/j.cell.2019.05.031 (2019).","journal-title":"Cell"},{"key":"89531_CR31","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","volume":"38","author":"D Warde-Farley","year":"2010","unstructured":"Warde-Farley, D. et al. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38, W214-220. https:\/\/doi.org\/10.1093\/nar\/gkq537 (2010).","journal-title":"Nucleic Acids Res."},{"key":"89531_CR32","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere, U. et al. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191-w198. https:\/\/doi.org\/10.1093\/nar\/gkz369 (2019).","journal-title":"Nucleic Acids Res."},{"key":"89531_CR33","doi-asserted-by":"crossref","unstructured":"Wickham, H. ggplot2 elegant graphics for data analysis. (2016).","DOI":"10.1007\/978-3-319-24277-4"},{"key":"89531_CR34","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1161\/circulationaha.111.039008","volume":"124","author":"J Fiedler","year":"2011","unstructured":"Fiedler, J. et al. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation 124, 720\u2013730. https:\/\/doi.org\/10.1161\/circulationaha.111.039008 (2011).","journal-title":"Circulation"},{"key":"89531_CR35","doi-asserted-by":"publisher","first-page":"520","DOI":"10.3389\/fphys.2020.00520","volume":"11","author":"SD Stojanovi\u0107","year":"2020","unstructured":"Stojanovi\u0107, S. D. et al. Inflammatory drivers of cardiovascular disease: Molecular characterization of senescent coronary vascular smooth muscle cells. Front. Physiol. 11, 520. https:\/\/doi.org\/10.3389\/fphys.2020.00520 (2020).","journal-title":"Front. Physiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89531-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89531-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89531-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T09:38:51Z","timestamp":1670060331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89531-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,14]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89531"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89531-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,6,14]]},"assertion":[{"value":"26 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"T.T. has filed and licensed patents regarding noncoding RNAs in CVD. T.T. is founder and shareholder of Cardior Pharmaceuticals GmbH. All other authors have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12456"}}