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| Status |
Public on Oct 01, 2018 |
| Title |
MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage |
| Organism |
Rattus norvegicus |
| Experiment type |
Non-coding RNA profiling by array
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| Summary |
Inflammatory b-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Proinflammatory cytokines cause b-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent b-cell failure in vitro and in vivo, in part by reducing NFkB transcriptional activity. Here we investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat prior to exposure to the proinflammatory cytokines IL-1-b and IFN-g for 6h or 24h, and miR expression was profiled with miR array. A shortlist of ten miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, and miR-455-5p) regulated by both cytokines and Givinostat was verified by qRT-PCR. MiR-146a-5p was strongly regulated by cytokines and KDACi and analyzed further. MiR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced the activity of NFκB and iNOS promoters, decreased NO production, and decreased protein levels of iNOS and its own direct target TNF receptor associated factor 6 (TRAF6). MiR-146a-5p was elevated in diabetes-prone BB-DP rat pancreas at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced b-cell apoptosis, demonstrating the strength of this approach.
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| Overall design |
miRNA gene expression in INS1 cells was measured at 6 and 24 hours with or without exposure to Givinostat and proinflammatory cytokines IL-1β and IFNγ. Eight independent experiments were performed with three technical replicates at each time (6 or 24 hours).
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| Contributor(s) |
Pociot F, Mandrup-Poulsen T |
| Citation(s) |
30260972 |
| Submission date |
Jul 20, 2018 |
| Last update date |
Jan 02, 2019 |
| Contact name |
Flemming Pociot |
| E-mail(s) |
flemming.pociot@regionh.dk
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| Organization name |
Steno Diabetes Center Copenhagen
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| Department |
T1D Biology
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| Street address |
Niels Steensens Vej 2
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| City |
Gentofte |
| ZIP/Postal code |
2820 |
| Country |
Denmark |
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| Platforms (1) |
| GPL22760 |
Agilent-070154 Rat miRNA Microarray (miRNA ID version version) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA482140 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE117451_RAW.tar |
43.1 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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