title: Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Medicine, University Hospital, CHUV, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: F
authors.initials: F
authors.lastname: Allagnat
authors.forename: G
authors.initials: G
authors.lastname: Chaffard
authors.forename: D
authors.initials: D
authors.lastname: Caille
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: R
authors.initials: R
authors.lastname: Regazzi
authors.forename: A
authors.initials: A
authors.lastname: Abderrahmani
authors.forename: G
authors.initials: G
authors.lastname: Waeber
authors.forename: P
authors.initials: P
authors.lastname: Meda
authors.forename: P
authors.initials: P
authors.lastname: Maechler
authors.forename: J-A
authors.initials: JA
authors.lastname: Haefliger
mesh_terms: D000818:Animals; D002843:Chromatin / Q000502:physiology; D016384:Consensus Sequence; D003600:Cytosol / Q000502:physiology; D020868:Gene Silencing; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002843:Chromatin; D005947:Glucose; D007328:Insulin; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor