title: Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2β, and GAD65.
abstract: Islet antigen (IA)-2, IA-2β, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA-2β, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens.
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA abuhatzira@mail.nih.gov.
authors.forename: Liron
authors.initials: L
authors.lastname: Abuhatzira
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Xu
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: Tahhan
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Afroditi
authors.initials: A
authors.lastname: Boulougoura
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: *Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Abner L
authors.initials: AL
authors.lastname: Notkins
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000276:immunology; D053487:DEAD-box RNA Helicases / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics
chemical_list: D001324:Autoantigens; D035683:MicroRNAs; D012333:RNA, Messenger; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D053487:DEAD-box RNA Helicases; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: autoimmune diabetes; glucose-sensitive; miR-342; miRNA