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| Status |
Public on Jan 19, 2017 |
| Title |
Artemisinins target GABA receptor signaling to induce alpha to beta cell transdifferentiation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Type 1 diabetes is characterized by the destruction of pancreatic beta cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types including glucagon-producing alpha cells. In a genetic model, overexpression of the master regulatory transcription factor Pax4 or loss of its counterplayer Arx are sufficient to induce the conversion of alpha cells to functional beta-like cells. Here we identify artemisinins as small molecules that functionally repress Arx and induce beta-cell characteristics in alpha cells. We show that the protein gephyrin is the mammalian target of these antimalaria drugs. Finally, we demonstrate that gephyrin-mediated enhancement of GABAA receptor signaling is the mechanism of action of these molecules in pancreatic transdifferentiation. Our results indicate that gephyrin is a novel druggable target for the regeneration of pancreatic beta cell mass from alpha cells.
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| Overall design |
Transcriptional dissection of Artemether treated, human pancreatic islets of one donor using single-cell RNA-seq
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| Contributor(s) |
Li J, Frogne T, Courtney M, Huber KV, Sturtzel C, Casteels T, Lardeau C, Klughammer J, Farlik M, Sdelci S, Baburin I, Kimmel RA, Majek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Barbieux C, Berishvili E, Spittler A, Colinge J, Bennett K, Meyer D, Hering S, Bock C, Distel M, Superti-Furga G, Collombat P, Hecksher-Sørensen J, Kubicek S |
| Citation(s) |
27916275 |
| Submission date |
Jul 22, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Christoph Bock |
| E-mail(s) |
cbock@cemm.oeaw.ac.at
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| Organization name |
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
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| Street address |
Lazarettgasse 14
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| City |
Vienna |
| ZIP/Postal code |
1090 |
| Country |
Austria |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA330917 |
| SRA |
SRP079357 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE84714_RAW.tar |
222.0 Mb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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