Identification of potential target genes for the neuron-restrictive silencer factor.

Schoenherr, Christopher J.; Paquette, Alice J.; Anderson, David J.

doi:10.1073/pnas.93.18.9881

Cited by 382 publications

(356 citation statements)

References 39 publications

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“…The 21 bp human RE-1 sequences associated to these genes were compared with those of consensus RE-1 and of the known CX36 RE-1 [11]. All sequences, except that of MUNC18-1, were closely homologous to the consensus one and displayed a typical core [23] consisting of two invariant domains (Fig. 5a).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2008

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“…NRSF\REST is known to be a 116 kDa protein [133] containing eight non-canonical zinc fingers [132], only one of which has been shown to be crucial for repression of the type II sodium channel gene [134]. Interestingly, several research groups have now identified NRSE-directed silencer activity in a variety of neuronal as well as non-neuronal genes [130][131][132][135][136][137][138][139][140][141].…”

Section: Nrsf/nrsementioning

confidence: 99%

Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes

Ogbourne

Antalis

1998

Biochemical Journal

227

171

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Mechanisms controlling transcription and its regulation are fundamental to our understanding of molecular biology and, ultimately, cellular biology. Our knowledge of transcription initiation and integral factors such as RNA polymerase is considerable, and more recently our understanding of the involvement of enhancers and complexes such as holoenzyme and mediator has increased dramatically. However, an understanding of transcriptional repression is also essential for a complete understanding of promoter structure and the regulation of gene expression. Transcriptional repression in eukaryotes is achieved through ‘silencers ’, of which there are two types, namely ‘silencer elements ’ and ‘negative regulatory elements ’ (NREs). Silencer elements are classical, position-independent elements that direct an active repression mechanism, and NREs are position-dependent elements that direct a passive repression mechanism. In addition, ‘repressors ’ are DNA-binding trasncription factors that interact directly with silencers. A review of the recent literature reveals that it is the silencer itself and its context within a given promoter, rather than the interacting repressor, that determines the mechanism of repression. Silencers form an intrinsic part of many eukaryotic promoters and, consequently, knowledge of their interactive role with enchancers and other transcriptional elements is essential for our understanding of gene regulation in eukaryotes.

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“…The NRSF is a repressor of a large number of neuronal terminal differentiation genes in non-neuronal tissues as well as neuronal stem cells reviewed in references. 24,[35][36][37][38][39][40] Studies with the neuronal n(AchR) b-2 subunit revealed a dual regulatory role of the NRSE. In transgenic mice, the NRSE functioned as either a repressor or enhancer depending on the cellular context in the neurons.…”

Section: Discussionmentioning

confidence: 99%

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

et al. 2012

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The INSM1 gene encodes a transcriptional repressor that is exclusively expressed in neuronal and neuroendocrine tissue during embryonic development that is re-activated in neuroendocrine tumors. Using the 1.7 kbp INSM1 promoter, an adenoviral HSV thymidine kinase gene therapy was tested for the treatment of neuroendocrine tumors. An unforeseen interference on the INSM1 promoter specificity from the adenoviral genome was observed. Attempts were made to protect the INSM1 promoter from the influence of essential adenoviral sequences and to further enhance the tissue specificity of the INSM1 promoter region. Using the chicken b-globin HS4 insulator sequence, we eliminated off-target tissue expression from the Ad-INSM1 promoter-luciferase2 constructs in vivo. In addition, inclusion of two copies of the mouse nicotinic acetylcholine receptor (n(AchR)) neuronal-restrictive silencer element (NRSE) reduced nonspecific activation of the INSM1 promoter both in vitro and in vivo. Further, inclusion of both the HS4 insulator with the n(AchR) 2 Â NRSE modification showed a two log increase in luciferase activity measured from the NCI-H1155 xenograft tumors compared with the original adenovirus construct. The alterations increase the therapeutic potential of adenoviral INSM1 promoter-driven suicide gene therapy for the treatment of a variety of neuroendocrine tumors.

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Identification of potential target genes for the neuron-restrictive silencer factor.

Cited by 382 publications

References 39 publications

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

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

Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

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