{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T13:28:50Z","timestamp":1778506130274,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Slovenian Research and Innovation Agency","award":["P3-0427"],"award-info":[{"award-number":["P3-0427"]}]},{"name":"Slovenian Research and Innovation Agency","award":["I0-0029"],"award-info":[{"award-number":["I0-0029"]}]},{"name":"Slovenian Research and Innovation Agency","award":["J3-9258"],"award-info":[{"award-number":["J3-9258"]}]},{"name":"Slovenian Research and Innovation Agency","award":["J3-4497"],"award-info":[{"award-number":["J3-4497"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Curated online interaction databases and gene ontology tools have streamlined the analysis of highly complex gene\/protein networks. However, understanding of disease pathogenesis has gradually shifted from a protein-based core to complex interactive networks where non-coding RNA (ncRNA) is thought to play an essential role. As current gene ontology is based predominantly on protein-level information, there is a growing need to analyze networks with ncRNA. In this study, we propose a gene ontology workflow integrating ncRNA using the NPInter V5.0 database. To validate the proposed workflow, we analyzed our previously published curated biomarker datasets for hidden disease susceptibility processes and pharmacogenomics. Our results show a novel involvement of melanogenesis in psoriasis response to biological drugs in general. Hyperpigmentation has been previously observed in psoriasis following treatment with currently indicated biological drugs, thus calling attention to melanogenesis research as a response biomarker in psoriasis. Moreover, our proposed workflow highlights the need to critically evaluate computed ncRNA interactions within databases and a demand for gene ontology analysis of large miRNA blocks.<\/jats:p>","DOI":"10.3390\/ijms251810210","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T09:15:07Z","timestamp":1727082907000},"page":"10210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of Novel Biomarkers with Extended Non-Coding RNA Interactor Networks from Genetic and Protein Biomarkers"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-5345","authenticated-orcid":false,"given":"Gregor","family":"Jezernik","sequence":"first","affiliation":[{"name":"Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"},{"name":"National-Level Institute for Sustainable Environmental Solutions, Jadranska cesta 28, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9912-3331","authenticated-orcid":false,"given":"Damjan","family":"Glava\u010d","sequence":"additional","affiliation":[{"name":"Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"},{"name":"Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Skok","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Internal Medicine Clinic, University Medical Centre Maribor, Ljubljanska ulica 8, 2000 Maribor, Slovenia"},{"name":"Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7921-6565","authenticated-orcid":false,"given":"Martina","family":"Kru\u0161i\u010d","sequence":"additional","affiliation":[{"name":"Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-9428","authenticated-orcid":false,"given":"Uro\u0161","family":"Poto\u010dnik","sequence":"additional","affiliation":[{"name":"Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"},{"name":"Department for Science and Research, University Medical Centre Maribor, Ljubljanska ulica 8, 2000 Maribor, Slovenia"},{"name":"Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4208-9683","authenticated-orcid":false,"given":"Mario","family":"Gorenjak","sequence":"additional","affiliation":[{"name":"Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D258","DOI":"10.1093\/nar\/gkh036","article-title":"The Gene Ontology (GO) database and informatics resource","volume":"32","author":"Harris","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Conte, F., Fiscon, G., Licursi, V., Bizzarri, D., D\u2019Ant\u00f2, T., Farina, L., and Paci, P. (2020). A paradigm shift in medicine: A comprehensive review of network-based approaches. Biochim. Biophys. Acta Gene Regul. Mech., 1863.","DOI":"10.1016\/j.bbagrm.2019.194416"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cell.2011.07.014","article-title":"A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language?","volume":"146","author":"Salmena","year":"2011","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nrg.2016.20","article-title":"Endogenous microRNA sponges: Evidence and controversy","volume":"17","author":"Thomson","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"D155","DOI":"10.1093\/nar\/gky1141","article-title":"miRBase: From microRNA sequences to function","volume":"47","author":"Kozomara","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1261\/rna.055301.115","article-title":"Guidelines for the functional annotation of microRNAs using the Gene Ontology","volume":"22","author":"Huntley","year":"2016","journal-title":"RNA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4563523","DOI":"10.1155\/2022\/4563523","article-title":"Comprehensive Analysis of Potential Biomarkers of Acute Lymphoblastic Leukemia in Children by Using a Competing Endogenous RNA Network","volume":"2022","author":"Lin","year":"2022","journal-title":"J. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3892\/ijmm.2021.5049","article-title":"lncRNA NORAD is consistently detected in breastmilk exosomes and its expression is downregulated in mothers of preterm infants","volume":"48","author":"Mourtzi","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e423","DOI":"10.1097\/CAD.0000000000001225","article-title":"Paeoniflorin inhibits proliferation and migration of psoriatic keratinocytes via the lncRNA NEAT1\/miR-3194-5p\/Galectin-7 axis","volume":"33","author":"Wang","year":"2022","journal-title":"Anticancer Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1080\/15476286.2023.2223486","article-title":"Implications of LncRNAs and CircRNAs in psoriasis: A review","volume":"20","author":"Shi","year":"2023","journal-title":"RNA Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3795","DOI":"10.1038\/s41467-023-39011-5","article-title":"The long non-coding RNA NEAT1 is a \u0394Np63 target gene modulating epidermal differentiation","volume":"14","author":"Fierro","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5980190","DOI":"10.1155\/2020\/5980190","article-title":"Immune Regulation of TNFAIP3 in Psoriasis through Its Association with Th1 and Th17 Cell Differentiation and p38 Activation","volume":"2020","author":"Jiang","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sahlol, N.Y., Mostafa, M.S., Madkour, L.A.E., and Salama, D.M. (2019). Low TNFAIP3 expression in psoriatic skin promotes disease susceptibility and severity. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0217352"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1750-1172-2-4","article-title":"Noonan syndrome","volume":"2","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yue, Y., Zhong, M., An, X., Feng, Q., Lai, Y., Yu, M., Zhang, X., Liao, Z., Chen, M., and Dong, J. (2022). Serotonin (5-HT) 2A Receptor Involvement in Melanin Synthesis and Transfer via Activating the PKA\/CREB Signaling Pathway. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116111"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.4049\/jimmunol.2100686","article-title":"ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation","volume":"207","author":"Arakawa","year":"2021","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jdermsci.2012.11.002","article-title":"NF-\u03baB: An essential transcription factor in psoriasis","volume":"69","author":"Goldminz","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/bjc.2011.249","article-title":"Functional and prognostic relevance of the homeobox protein MSX2 in malignant melanoma","volume":"105","author":"Gremel","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Marin Lovri\u0107, J., Filipovi\u0107, N., Znaor, L., Ran\u010di\u0107, A., Petri\u010devi\u0107, J., Kunac, N., \u0160olji\u0107, V., Saraga-Babi\u0107, M., and Vukojevi\u0107, K. (2022). Expression of Cell Cycle Markers and Proliferation Factors during Human Eye Embryogenesis and Tumorigenesis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169421"},{"key":"ref_20","first-page":"e32264","article-title":"Erythema Dyschromicum Perstans After Adalimumab Treatment","volume":"14","author":"Alsisi","year":"2022","journal-title":"Cureus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"632","DOI":"10.5144\/0256-4947.2013.632","article-title":"Recalcitrant psoriasis responding to new bilogic drug: Ustekinumab","volume":"33","year":"2013","journal-title":"Ann. Saudi Med."},{"key":"ref_22","first-page":"22338","article-title":"Multiple lentigines in areas of resolving psoriatic plaques after ustekinumab therapy","volume":"20","author":"Batalla","year":"2014","journal-title":"Dermatol. Online J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ajhg.2011.11.019","article-title":"Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy","volume":"90","author":"Zhang","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jcmgh.2021.03.005","article-title":"Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver\u2019s Seat","volume":"12","author":"Prasad","year":"2021","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11573","DOI":"10.1073\/pnas.0913138107","article-title":"A kinesin signaling complex mediates the ability of GSK-3beta to affect mood-associated behaviors","volume":"107","author":"Du","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Arciniegas Ruiz, S.M., and Eldar-Finkelman, H. (2021). Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.792364"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1073\/pnas.0708022105","article-title":"Lithium delays progression of amyotrophic lateral sclerosis","volume":"105","author":"Fornai","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S1474-4422(13)70037-1","article-title":"Lithium in patients with amyotrophic lateral sclerosis (LiCALS): A phase 3 multicentre, randomised, double-blind, placebo-controlled trial","volume":"12","author":"Morrison","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1212\/WNL.0000000000004606","article-title":"Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials","volume":"89","author":"Jones","year":"2017","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1046\/j.1471-4159.2003.01670.x","article-title":"Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord","volume":"85","author":"Hu","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.brainres.2007.12.031","article-title":"Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci)","volume":"1196","author":"Yang","year":"2008","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1016\/j.celrep.2018.04.045","article-title":"GSK3\u03b2 Regulates Brain Energy Metabolism","volume":"23","author":"Martin","year":"2018","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40478-019-0658-x","article-title":"ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles","volume":"7","author":"An","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ebiom.2017.06.023","article-title":"CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer","volume":"21","author":"Binothman","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9300","DOI":"10.18632\/aging.204407","article-title":"The roles of CPSF6 in proliferation, apoptosis and tumorigenicity of lung adenocarcinoma","volume":"14","author":"Zu","year":"2022","journal-title":"Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1515\/med-2022-0570","article-title":"Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT\/mTOR signaling pathway","volume":"17","author":"An","year":"2022","journal-title":"Open Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6334","DOI":"10.1038\/s41467-023-41861-y","article-title":"CSTF2 mediated mRNA N","volume":"14","author":"Zheng","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"773","DOI":"10.21037\/atm-21-34","article-title":"LncRNA NEAT1 mediates intestinal inflammation by regulating TNFRSF1B","volume":"9","author":"Pan","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_40","first-page":"2903","article-title":"Inhibition of lncRNA NEAT1 suppresses the inflammatory response in IBD by modulating the intestinal epithelial barrier and by exosome-mediated polarization of macrophages","volume":"42","author":"Liu","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ncrna.2024.01.012","article-title":"Expression profile of serum LncRNAs","volume":"9","author":"Ali","year":"2024","journal-title":"Noncoding RNA Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"445","DOI":"10.2217\/pme-2020-0009","article-title":"Increase in MEG3, MALAT1, NEAT1 significantly predicts the clinical parameters in patients with rheumatoid arthritis","volume":"17","author":"Chatterjee","year":"2020","journal-title":"Per. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D232","DOI":"10.1093\/nar\/gkac1002","article-title":"NPInter v5.0: ncRNA interaction database in a new era","volume":"51","author":"Zheng","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/pro.3978","article-title":"The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions","volume":"30","author":"Oughtred","year":"2021","journal-title":"Protein Sci."},{"key":"ref_45","unstructured":"Coutin, N. (2024, February 19). biogridr: BioGRID R API. Available online: https:\/\/github.com\/npjc\/biogridr."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jezernik, G., Mi\u010deti\u0107-Turk, D., and Poto\u010dnik, U. (2020). Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040243"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jezernik, G., Gorenjak, M., and Poto\u010dnik, U. (2022). Gene Ontology Analysis Highlights Biological Processes Influencing Non-Response to Anti-TNF Therapy in Rheumatoid Arthritis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081808"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kru\u0161i\u010d, M., Jezernik, G., and Poto\u010dnik, U. (2023). Gene Ontology Analysis Highlights Biological Processes Influencing Responsiveness to Biological Therapy in Psoriasis. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15082024"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Glava\u010d, D., Mladini\u0107, M., Ban, J., Mazzone, G.L., S\u00e1mano, C., Tomljanovi\u0107, I., Jezernik, G., and Ravnik-Glava\u010d, M. (2022). The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911360"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:00:27Z","timestamp":1760112027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":51,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms251810210"],"URL":"https:\/\/doi.org\/10.3390\/ijms251810210","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,23]]}}}