Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

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Serval ID
serval:BIB_C799305903FC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells
Journal
Diabetologia
Author(s)
Martin D., Allagnat F., Chaffard G., Caille D., Fukuda M., Regazzi R., Abderrahmani A., Waeber G., Meda P., Maechler P., Haefliger J. A.
ISSN
0012-186X
Publication state
Published
Issued date
08/2008
Peer-reviewed
Oui
Volume
51
Number
8
Pages
1429-1439
Language
english
Notes
Journal article --- Old month value: Apr 3, online publication date
Abstract
AIMS/HYPOTHESIS: The expression of several neuronal genes in pancreatic beta cells is due to the absence of the transcription factor repressor element 1 (RE-1) silencing transcription factor (REST). The identification of these traits and their functional significance in beta cells has only been partly elucidated. Herein, we investigated the biological consequences of a repression of REST target genes by expressing REST in beta cells. METHODS: The effect of REST expression on glucose homeostasis, insulin content and release, and beta cell mass was analysed in transgenic mice selectively expressing REST in beta cells. Relevant target genes were identified in INS-1E and primary beta cells expressing REST. RESULTS: Transgenic mice featuring a beta cell-targeted expression of REST exhibited glucose intolerance and reduced beta cell mass. In primary beta cells, REST repressed several proteins of the exocytotic machinery, including synaptosomal-associated protein (SNAP) 25, synaptotagmin (SYT) IV, SYT VII, SYT IX and complexin II; it impaired first and second phases of insulin secretion. Using RNA interference in INS-1E cells, we showed that SYT IV and SYT VII were implicated in the control of insulin release. CONCLUSIONS/INTERPRETATION: The data document the critical role of REST target genes in pancreatic beta cells. Specifically, we provide evidence that the downregulation of these genes is detrimental for the exocytosis of large dense core vesicles, thus contributing to beta cell dysfunction and impaired glucose homeostasis.
Keywords
Exocytosis, Insulin secretion, RE-1, RE-1 silencing transcription factor, REST, Synaptotagmins, Transgenic mice
Pubmed
Web of science
Open Access
Yes
Create date
13/05/2008 14:57
Last modification date
28/04/2021 6:33
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