title: The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.
abstract: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA-seq) to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ). Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the immune system and beta cell level.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium. deizirik@ulb.ac.be
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Michael
authors.initials: M
authors.lastname: Sammeth
authors.forename: Thomas
authors.initials: T
authors.lastname: Bouckenooghe
authors.forename: Guy
authors.initials: G
authors.lastname: Bottu
authors.forename: Giorgia
authors.initials: G
authors.lastname: Sisino
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ortis
authors.forename: Izortze
authors.initials: I
authors.lastname: Santin
authors.forename: Maikel L
authors.initials: ML
authors.lastname: Colli
authors.forename: Jenny
authors.initials: J
authors.lastname: Barthson
authors.forename: Luc
authors.initials: L
authors.lastname: Bouwens
authors.forename: Linda
authors.initials: L
authors.lastname: Hughes
authors.forename: Lorna
authors.initials: L
authors.lastname: Gregory
authors.forename: Gerton
authors.initials: G
authors.lastname: Lunter
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D007107:Immune System; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics
chemical_list: D007328:Insulin; D053583:Interleukin-1beta; D007371:Interferon-gamma