BCAS2 is involved in insulin synthesis and secretion by mRNA alternative splicing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA931314 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23335428_1.fastq.gz | Fastqsanger.gz | |||
| SRR23335428_2.fastq.gz | Fastqsanger.gz | |||
| SRR23335429_1.fastq.gz | Fastqsanger.gz | |||
| SRR23335429_2.fastq.gz | Fastqsanger.gz | |||
| SRR23335430_1.fastq.gz | Fastqsanger.gz |
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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:BCAS2 (Breast cancer amplified sequence 2) is involved in multiple biological processes, including pre-mRNA splicing. However, the physiological roles of BCAS2 are still largely unclear. Here we report that BCAS2 is specifically enriched in spermatogonia of mouse testes. Conditional disruption of Bcas2 in male germ cells impairs spermatogenesis and leads to male mouse infertility. Although the spermatogonia appear grossly normal, spermatocytes in meiosis prophase I and meiosis events (recombination and synapsis) are rarely observed in the BCAS2-depleted testis. In BCAS2 null testis, 245 genes are altered in alternative splicing forms; at least three spermatogenesis-related genes (Dazl, Ehmt2 and Hmga1) can be verified. In addition, disruption of Bcas2 results in a significant decrease of the full-length form and an increase of the short form (lacking exon 8) of DAZL protein. Altogether, our results suggest that BCAS2 regulates alternative splicing in spermatogonia and the transition to meiosis initiation, and male fertility.
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Project description:Modulation of insulin secretion through RBFOX2-mediated alternative splicing
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Project description:Oocyte meiosis is an important factor affecting female reproduction. Breast cancer amplified sequence 2 (BCAS2) is a component of the spliceosome. Previous reports have shown that BCAS2 is critical in male germ cell meiosis, oocyte development, and early embryo genome integrity. However, the role of BCAS2 in oocyte meiosis has not been reported. We used Stra8-GFP-Cre mice to knock out BCAS2 during the pachytene phase of oocytes. The results of fertility tests showed that the cko mice were infertile. Morphological analysis showed that the number of primary follicles of 2M ovary was significantly reduced and follicle development was blocked. Further analysis showed that the number of primordial follicles decreased and follicle development slowed from 7dpp ovaries. Sequencing revealed that DNA damage in oocytes could not be repaired from 5dpp. There was an abnormality in meiosis, some oocytes could not reach the diplotene stage of meiosis, and more oocytes could not develop to the dictyate stage. AS analysis reveals that abnormal variable splicing of Dazl and Diaph2 Oogens-related genes in cKO mice, with involvement of the PRP19/CDC5l complex.
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Project description:DDX1 regulates alternative splicing and insulin secretion in pancreatic β cells
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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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