A role for alternative splicing in circadian control of insulin secretion and glucose homeostasis
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ABSTRACT:
PROVIDER: PRJNA612358 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11300801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11300801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11300802_1.fastq.gz | Fastqsanger.gz | |||
| SRR11300802_2.fastq.gz | Fastqsanger.gz | |||
| SRR11300803_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the discovery of circadian clock-controlled alterantive pre-mRNA splicing in pancreatic beta cells and its role in insulin secretion. We performed RNA-sequencing in CRISPR-CAS9 edited Clock and Bmal1 knockout BetaTC6 cells and used differential mRNA expression and splicing analysis to identify and validate transcriptional and alternative splicing targets of the circadian clock regulating insulin secretion.
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Project description:Insulin secreted by pancreatic β cells is essential for maintaining the level of blood glucose. Diabetes is mainly caused by the loss of β cells or impaired β cell function. The previous study performed a whole transcriptome analysis on the islets of T2D and the control group, and the results showed that the splicing disorder of the splicing event was about 25%, breast carcinoma amplified sequence 2(BCAS2) is one of the components of the spliceosome, and its function in islet β cell is unclear. Here we report that knockdown of Bcas2 decreases in glucose and KCl-stimulated insulin secretion in the NIT-1 cell line. The pancreas weight, glucose tolerance and insulin sensitivity were detected in normal chow-fed and high-fat diet-fed Bcas2 f/f-βKO mice, and β cell mass and islet size was analyzed by immunohistochemistry. Glucose intolerance developed in Bcas2 f/f-βKO mice, but there were no significant differences in pancreas weight, insulin sensitivity, β cell mass and islet size. Further, GSIS and observation of insulin secretion granules were performed on normal chow-fed mice, and it was found that the insulin level in serum decreased and the number of insulin secretion granules decreased in Bcas2 f/f-βKO mice, which was related to the abnormal splicing of Syt7 and Tcf7l2 pre-mRNA. Taken together, these results demonstrate that BCAS2 is involved in alternative splicing during insulin synthesis and secretion. Elisa,islet isolation,insulin secretion
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Project description:Pancreatic beta-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair beta-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on beta-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during beta-cell glucose toxicity that impairs expression of proteins with critical roles in beta-cell function.
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