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The Human Pancreatic Islet Transcriptome: Expression of Candidate Genes for Type 1 Diabetes and the Impact of Pro-Inflammatory Cytokines
Journal Contribution - Journal Article
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-
1b (IL-1b) and interferon-c (IFN-c). 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.
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-
1b (IL-1b) and interferon-c (IFN-c). 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.
Journal: PLoS Genet
ISSN: 1553-7390
Issue: 3
Volume: 8
Pages: 1-17
Publication year:2012
Keywords:pancreas, islets of Langerhans, beta-cells, transcriptome, diabetes