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| Status |
Public on Oct 03, 2021 |
| Title |
Progressive ER stress over time due to human insulin gene mutation contributes to pancreatic β-cell dysfunction, islet inflammation and compensatory responses |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Heterozygous human INS gene mutations are known to promote ER stress, leading to β-cell dysfunction and neonatal diabetes. Recent literature challenged the long-standing notion that neonatal diabetes occurs due to ER stress-induced β-cell apoptosis. Importantly, mechanisms of β-cell failure during the disease progression and why the other wild-type (WT) INS allele is unable to function still remain unclear. Here, our computational modelling studies, short-term and long-term expression studies in β-cells revealed the presence of ER stress, organelle changes and insulin processing defects, resulting in decreased insulin secretion but not insulin secretory capacity. By nine weeks of expression of mutant INS, dominant negative effects of mutant INS were evident and β-cell insulin secretory capacity declined. INS+/C109Y patient-derived β-like cells and single cell RNA-Sequencing analyses then revealed compensatory upregulation in genes involved in insulin secretion, processing and inflammatory response. Our results provide deeper insights into the mechanisms of β-cell failure during INS mutation-mediated diabetes disease progression. Decreasing CHOP-10, sXBP1 or inflammatory response could be avenues to restore the function of the remaining WT INS allele.
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| Overall design |
To identify genome-wide transcriptomic perturbations caused by INS+/C109Y mutation, we performed single-cell RNA-Seq analyses on the hiPSC-derived β-like cells
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| Contributor(s) |
Amirruddin NS, Tan YS, Gardner D, Yong MB, Verma CS, Hoon S, Lee KO, Teo AK |
| Citation(s) |
34448879 |
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| Submission date |
Dec 02, 2019 |
| Last update date |
Jan 02, 2022 |
| Contact name |
Adrian Kee Keong Teo |
| E-mail(s) |
ateo@imcb.a-star.edu.sg
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| Organization name |
IMCB, A*STAR
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| Department |
Stem Cells and Diabetes Laboratory
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| Street address |
61 Biopolis Drive, Proteos
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| City |
Singapore |
| State/province |
Singapore |
| ZIP/Postal code |
138673 |
| Country |
Singapore |
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| Platforms (1) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA593046 |
| SRA |
SRP234455 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE141319_WT_HET_normalized.h5 |
32.7 Mb |
(ftp)(http) |
H5 |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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