Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA759781 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15697732_1.fastq.gz | Fastqsanger.gz | |||
| SRR15697732_2.fastq.gz | Fastqsanger.gz | |||
| SRR15697733_1.fastq.gz | Fastqsanger.gz | |||
| SRR15697733_2.fastq.gz | Fastqsanger.gz | |||
| SRR15697734_1.fastq.gz | Fastqsanger.gz |
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Project description:Alternative splicing (AS) within the β cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1β + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS events. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. AS events occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB, while RNA FISH confirmed HLA-DMB splicing in pancreatic sections from human T1D donors. Together, these data suggest that dynamic control of AS plays a role in the β cell response to inflammatory signals during T1D evolution.
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Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688â700, 2003 Experiment Overall Design: Four B6-ob/ob and four BTBR-ob/ob male mice at 14 weeks of age were used in the microarray study. RNA samples from two individuals were pooled for each tissue, and each pooled RNA sample was applied to an Affymetrix MGU74AV2 array. Because of the scarcity of islets in the BTBR-ob/ob mice, 4 additional mice were pooled to obtain islet RNA from these animals. Sixteen MGU74Av2 arrays (2 strains X 4 tissues X 2 replicates = 16 arrays) were used to monitor the expression level of â12,000 genes or ESTs.
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