RNA-seq-based identification of StAR upregulation by islet amyloid formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA558147 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9887140.fastq.gz | Fastqsanger.gz | |||
| SRR9887150.fastq.gz | Fastqsanger.gz | |||
| SRR9887160.fastq.gz | Fastqsanger.gz | |||
| SRR9887141.fastq.gz | Fastqsanger.gz | |||
| SRR9887151.fastq.gz | Fastqsanger.gz |
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Project description:Aggregation of islet amyloid polypeptide (IAPP) into islet amyloid results in β-cell toxicity in human type 2 diabetes. To determine the effect of islet amyloid formation on gene expression, we performed RNA-seq analysis using cultured islets from either wild-type mice (mIAPP), which are not amyloid prone, or mice that express human IAPP (hIAPP), which develop amyloid. Comparing mIAPP and hIAPP islets, 5025 genes were differentially regulated (2439 upregulated and 2586 downregulated). When considering gene sets (reactomes), 248 and 52 pathways were up- and downregulated, respectively. Of the top 100 genes upregulated under two conditions of amyloid formation, seven were common. Of these seven genes, only steroidogenic acute regulatory protein AQ2 (Star) demonstrated no effect of glucose per se to modify its expression. We confirmed this differential gene expression using quantitative reverse transcription polymerase chain reaction and also demonstrated the presence of StAR protein in islets containing amyloid. Furthermore, Star is a part of reactomes representing metabolism, metabolism of lipids, metabolism of steroid hormones, metabolism of steroids and pregnenolone biosynthesis. Thus, examining gene expression that is differentially regulated by islet amyloid has the ability to identify new molecules involved in islet physiology and pathology applicable to type 2 diabetes.
2019-08-29 | GSE135276 | GEO
Project description:Aggregation of islet amyloid polypeptide (IAPP) into islet amyloid results in β-cell toxicity in human type 2 diabetes. To determine the effect of islet amyloid formation on gene expression, we performed ribonucleic acid (RNA) sequencing (RNA-seq) analysis using cultured islets from either wild-type mice (mIAPP), which are not amyloid prone, or mice that express human IAPP (hIAPP), which develop amyloid. Comparing mIAPP and hIAPP islets, 5025 genes were differentially regulated (2439 upregulated and 2586 downregulated). When considering gene sets (reactomes), 248 and 52 pathways were up- and downregulated, respectively. Of the top 100 genes upregulated under two conditions of amyloid formation, seven were common. Of these seven genes, only steroidogenic acute regulatory protein (Star) demonstrated no effect of glucose per se to modify its expression. We confirmed this differential gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and also demonstrated the presence of STAR protein in islets containing amyloid. Furthermore, Star is a part of reactomes representing metabolism, metabolism of lipids, metabolism of steroid hormones, metabolism of steroids and pregnenolone biosynthesis. Thus, examining gene expression that is differentially regulated by islet amyloid has the ability to identify new molecules involved in islet physiology and pathology applicable to type 2 diabetes.
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Project description:Amyloid fibrils formed by the islet amyloid polypeptide (IAPP) cause pancreatic beta-cell damage, resulting in reduced insulin secretion and Type 2 diabetes (T2D). Variations in the primary amino acid sequence of IAPP can influence its aggregation rate and animals expressing IAPP variants that do not form amyloids, do not develop T2D. Conversely, specific single amino -acid changes in IAPP are enough to accelerate its aggregation rate. Understanding how mutations impact IAPP aggregation can help gain mechanistic understanding into the process of pathogenic amyloid formation of this peptide and preventively identify mutations that may contribute to the risk of developing T2D. Here, we employ deep mutational scanning to measure the ability to nucleate amyloids for 1663 IAPP variants, including substitutions, insertions, truncations and deletions and identify variants that increase amyloid formation in all mutation classes. Our results point at a continuous stretch of residues (15-32) which likely is structured in IAPP amyloids and that matches the core of the early aggregated species formed by IAPP in vitro. Inside this region, mutations have a more drastic effect in the 21-27 NNFGAIL segment, suggesting tighter structural constraints for this stretch in IAPP amyloids. Finally, by comparing this mutational atlas to that of another amyloid, Amyloid beta (Aβ42), the peptide that aggregates in Alzheimer’s Disease, we find that the effects of mutations that slow down nucleation correlate between the two amyloids, but that when it comes to mutations that accelerate nucleation one single amyloid dataset cannot be used to predict mutational effects in the other.
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Project description:Complement inhibitor C4b-binding protein (C4BP) is synthesized in liver and pancreas and composed of 7 identical alpha chains and one unique beta chain. We showed previously that C4BP binds islet amyloid polypeptide (IAPP) and affects fibril formation in vitro. Now we found that polymeric C4BP inhibited lysis of human erythrocytes incubated with monomeric IAPP while no erythrocyte lysis was observed after incubation with preformed IAPP fibrils. In contrast, monomeric alpha chain of C4BP had significantly reduced activity. Further, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Accordingly, addition of C4BP rescued the ability of INS-1 cells and isolated rat islets to respond to glucose stimulation with insulin secretion, which was impaired in the presence of IAPP alone. C4BP was internalized together with IAPP into INS-1 cells and therefore we aimed to study its effect on gene expression. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison to IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-β-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-κB had a similar effect. Taken together, one of the mechanisms by which C4BP protects beta-cells from IAPP cytotoxicity is by enhancing cholesterol synthesis. The INS-1 cells were grown as 5 separate clones for 10 passages before plating in a 12-well plate (Nunc) at 100.000 cells per well and grown in complete RPMI 1640 medium to 70% confluency for approximately 48 h. The cells were then challenged by adding 77 μM monomeric IAPP alone or together with C4BP (0.6 μM). DMSO (1%) used as solvent for IAPP as well as C4BP (0.6 μM) alone were used as controls. RNA was extracted after 10h incubation and analysis carried out using Rat Gene 2.0 array chip (Affymetrix).
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Project description:Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation
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