{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:40:00Z","timestamp":1787748000036,"version":"build-2784847793"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014915","name":"Juvenile Diabetes Research Foundation Netherlands","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003092","name":"Diabetes Fonds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003092","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using high-throughput RNA sequencing data from human islets and EndoC-\u03b2H1 cells exposed to IFN\u03b1 or IFN\u03b3\/IL1\u03b2, we evaluated the role of ADAR1 in human pancreatic \u03b2 cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that both IFN\u03b1 and IFN\u03b3\/IL1\u03b2 stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-\u03b2H1 cells as well as in primary human islets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFN\u03b1 effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the \u03b2\u00a0cell transcriptome under inflammatory conditions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.1058345","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T07:10:31Z","timestamp":1669619431000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["ADAR1-dependent editing regulates human \u03b2\u00a0cell transcriptome diversity during inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Florian","family":"Szymczak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni","family":"Cohen-Fultheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Thomaidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra Coomans","family":"de Brach\u00e8ne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Castela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maikel","family":"Colli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Marchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erez","family":"Levanon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Decio","family":"Eizirik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Zaldumbide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.abd7600","article-title":"Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis","volume":"7","author":"Szymczak","year":"2021","journal-title":"Sci Adv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.tim.2018.08.007","article-title":"A balancing act: Mda5 in antiviral immunity and autoinflammation","volume":"27","author":"Dias Junior","year":"2019","journal-title":"Trends Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01763","article-title":"Adar1: \u201cEditor-in-Chief\u201d of cytoplasmic innate immunity","volume":"10","author":"Lamers","year":"2019","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1416-1","article-title":"The role of rna editing by Adar1 in prevention of innate immune sensing of self-rna","volume":"94","author":"Heraud-Farlow","year":"2016","journal-title":"J Mol Med (Berl)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2414","article-title":"Mutations in Adar1 cause aicardi-goutieres syndrome associated with a type I interferon signature","volume":"44","author":"Rice","year":"2012","journal-title":"Nat Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/1010428317734816","article-title":"Adar1 expression is associated with tumour-infiltrating lymphocytes in triple-negative breast cancer","volume":"39","author":"Song","year":"2017","journal-title":"Tumour Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.036","article-title":"Increased rna editing may provide a source for autoantigens in systemic lupus erythematosus","volume":"23","author":"Roth","year":"2018","journal-title":"Cell Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure","volume":"16","author":"Eizirik","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1007\/s00125-020-05176-7","article-title":"Presumption of innocence for beta cells: Why are they vulnerable autoimmune targets in type 1 diabetes","volume":"63","author":"Mallone","year":"2020","journal-title":"Diabetologia"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/biomedicines9020202","article-title":"Non-genetically encoded epitopes are relevant targets in autoimmune diabetes","volume":"9","author":"Nguyen","year":"2021","journal-title":"Biomedicines"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.667989","article-title":"Neoepitopes in type 1 diabetes: Etiological insights, biomarkers and therapeutic targets","volume":"12","author":"Rodriguez-Calvo","year":"2021","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1186\/s12967-019-2071-4","article-title":"Rna editing in the forefront of epitranscriptomics and human health","volume":"17","author":"Christofi","year":"2019","journal-title":"J Transl Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/s41467-020-14621-5","article-title":"Cis- and trans-regulations of pre-mrna splicing by rna editing enzymes influence cancer development","volume":"11","author":"Tang","year":"2020","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.593989","article-title":"Systematically characterizing a-to-I rna editing neoantigens in cancer","volume":"10","author":"Zhou","year":"2020","journal-title":"Front Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.cmet.2018.07.007","article-title":"Conventional and neo-antigenic peptides presented by beta cells are targeted by circulating naive Cd8+ T cells in type 1 diabetic and healthy donors","volume":"28","author":"Gonzalez-Duque","year":"2018","journal-title":"Cell Metab"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/microorganisms8091419","article-title":"Type 1 diabetes: Interferons and the aftermath of pancreatic beta-cell enteroviral infection","volume":"8","author":"Akhbari","year":"2020","journal-title":"Microorganisms"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.568446","article-title":"Molecular footprints of the immune assault on pancreatic beta cells in type 1 diabetes","volume":"11","author":"Colli","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58447","article-title":"A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion","volume":"121","author":"Ravassard","year":"2011","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1145\/2808719.2811568","article-title":". super deduper, fast pcr duplicate detection in fastq files","volume-title":"Proceedings of the 6th ACM conference on bioinformatics, computational biology and health informatics;","author":"Petersen","year":"2015"},{"key":"B20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"Star: Ultrafast universal rna-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0610-9","article-title":"Genome-wide quantification of adar adenosine-to-Inosine rna editing activity","volume":"16","author":"Roth","year":"2019","journal-title":"Nat Methods"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.12688\/f1000research.7035.1","article-title":"Rna-seq workflow: Gene-level exploratory analysis and differential expression","volume":"4","author":"Love","year":"2015","journal-title":"F1000Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.12688\/f1000research.7563.2","article-title":"Differential analyses for rna-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560","article-title":"Fastp: An ultra-fast all-in-One fastq preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat Methods"},{"key":"B26","doi-asserted-by":"publisher","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":"B27","doi-asserted-by":"publisher","first-page":"060012","DOI":"10.1101\/060012","article-title":"Fast gene set enrichment analysis","author":"Korotkevich","year":"2021","journal-title":"bioRxiv"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: An r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2003.11.021","article-title":"Lentiviral vectors efficiently transduce quiescent mature 3t3-L1 adipocytes","volume":"9","author":"Carlotti","year":"2004","journal-title":"Mol Ther"},{"key":"B30","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jaut.2018.08.003","article-title":"Interferon alpha: The key trigger of type 1 diabetes","volume":"94","author":"Lombardi","year":"2018","journal-title":"J Autoimmun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.3.531","article-title":"Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus","volume":"185","author":"von Herrath","year":"1997","journal-title":"J Exp Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2584","DOI":"10.1038\/s41467-020-16327-0","article-title":"An integrated multi-omics approach identifies the landscape of interferon-Alpha-Mediated responses of human pancreatic beta cells","volume":"11","author":"Colli","year":"2020","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0524-6","article-title":"The impact of proinflammatory cytokines on the beta-cell regulatory landscape provides insights into the genetics of type 1 diabetes","volume":"51","author":"Ramos-Rodriguez","year":"2019","journal-title":"Nat Genet"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/gr.164749.113","article-title":"A-to-I rna editing occurs at over a hundred million genomic sites, located in a majority of human genes","volume":"24","author":"Bazak","year":"2014","journal-title":"Genome Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"4726","DOI":"10.1038\/ncomms5726","article-title":"A genome-wide map of hyper-edited rna reveals numerous new sites","volume":"5","author":"Porath","year":"2014","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.991632","article-title":"Er stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis","volume":"13","author":"Vig","year":"2022","journal-title":"Front Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.09.040","article-title":"Pdl1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-alpha and-gamma Via Irf1 induction","volume":"36","author":"Colli","year":"2018","journal-title":"EBioMedicine"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-00443-4","article-title":"Type 1 diabetes mellitus as a disease of the beta-cell (Do not blame the immune system)","volume":"17","author":"Roep","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.stem.2020.04.016","article-title":"Adar1-dependent rna editing promotes met and ipsc reprogramming by alleviating er stress","volume":"27","author":"Guallar","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/bies.201700129","article-title":"The other face of an Editor: Adar1 functions in editing-independent ways","volume":"39","author":"Licht","year":"2017","journal-title":"Bioessays"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.16.6956-6963.2005","article-title":"Adar1 interacts with Nf90 through double-stranded rna and regulates Nf90-mediated gene expression independently of rna editing","volume":"25","author":"Nie","year":"2005","journal-title":"Mol Cell Biol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nrm.2015.4","article-title":"A-to-I editing of coding and non-coding rnas by adars","volume":"17","author":"Nishikura","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102267","article-title":"Rna binding by Adar3 inhibits adenosine-to-Inosine editing and promotes expression of immune response protein mavs","volume":"298","author":"Raghava Kurup","year":"2022","journal-title":"J Biol Chem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.748335","article-title":"Neuron-enriched rna-binding proteins regulate pancreatic beta cell function and survival","volume":"292","author":"Juan-Mateu","year":"2017","journal-title":"J Biol Chem"},{"key":"B45","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41419-019-2160-6","article-title":"Cell death following the loss of Adar1 mediated a-to-I rna editing is not effected by the intrinsic apoptosis pathway","volume":"10","author":"Walkley","year":"2019","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1058345\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T07:10:35Z","timestamp":1669619435000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1058345\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":45,"alternative-id":["10.3389\/fendo.2022.1058345"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.1058345","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,28]]},"article-number":"1058345"}}