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

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.

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

“…This is in line with previous studies showing that XBP1s is not required for normal development of islets [40] while it is essential to development of liver [35] and plasma cells [41]. A recent report also suggests that XBP1s is dispensable in neurons [42], which share many features with beta cells [43,44].…”

No REST for healthy beta cells

“…This repressor is known to prevent the transcription of neuronal genes in most cell types [3] other than beta cells and neurons, which are almost completely devoid of the REST protein [2,3]. In this commentary we will provide a brief review of the biological effects of REST, followed by a discussion of the work of Martin et al [1]. A large number of studies indicate that REST plays a key role in the establishment of the neuronal phenotype [4] and functions as a transcriptional repressor of neuronal genes in non-neuronal tissues.…”

“…To further study the function of the physiologically very low expression of REST in pancreatic beta cells, Martin et al [1] used genetically modified mice (referred to as RIP-REST throughout the remainder of this commentary) in which expression of human REST mRNA was selectively induced in beta cells under control of the rat Ins2 promoter. As expected, REST protein accumulated in the nuclei of the transgenic animals.…”

“…As in other secreting cells, many different proteins on the secretory vesicle membrane and plasma membrane are involved in signal-induced granule fusion and release of insulin into the extracellular space (reviewed in [11]). Martin et al [1] used bioinformatic tools, screening all predicted REST-reponsive genes for those that act at the level of exocytosis and contain a promoter element that resembles the known 21 bp human RE-1. This revealed a handful of target genes likely to account for the transgenic phenotype, notably the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein known as synaptosomal-associated protein 25 (SNAP25) and the Ca 2+ -sensitive synaptotagmins IV and VII (SYT4 and SYT7).…”

“…For SNAP25 and SYT4 further evidence for REST repression was found at the protein level. The main conclusion drawn by the authors of the paper [1] is that, in adult differentiated beta cells, REST expression should be avoided, because the repressor interferes with full expression of genes encoding important proteins of the exocytotic machinery.…”