Multiple transcripts of sodium channel SCN8A (NaV1.6) with alternative 5′- and 3′-untranslated regions and initial characterization of the SCN8A promoter

Drews, Valerie L.; Lieberman, Andrew P.; Meisler, Miriam H.

doi:10.1016/j.ygeno.2004.09.002

Cited by 30 publications

(38 citation statements)

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“…AC 000045). Transcriptional elements and factors were predicted using the PROMO program and the version 8.3 of TRANSFAC (http://alggen.lsi.upc.es/; Messeguer et al, 2002;Farre et al, 2003;Drews et al, 2005).…”

Section: Biosoftware Analysesmentioning

confidence: 99%

“…Among the CNS-specific sodium channel genes, the promoter regions of human SCN2A and SCN8A have been previously described (Lu et al, 1998;Schade and Brown, 2000;Yu and Catterall, 2003;Drews et al, 2005), but the promoter region of human SCN1A has not been reported to date. The aim of the present study was to identify the promoter region of SCN1A and the 5 0 -untranslated regions (5 0 -UTRs) that may affect the expression of SCN1A and to provide a basis for the search for those patients or diseases caused by Na v 1.1 insufficiency.…”

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confidence: 99%

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Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Long

Zhao

et al. 2008

J of Neuroscience Research

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Voltage-gated sodium channels play critical roles in the excitability of the brain. A decreased level of Na(v)1.1 has been identified as the cause of severe myoclonic epilepsy in infancy. In the present study, we identified the transcription start site and three 5'-untranslated exons of SCN1A by using 5'-full RACE. The 2.5-kb region upstream of the transcription start site was targeted as a potential location of the promoter. The 2.5-kb genomic fragment (P(2.5), from +26 to -2,500) and the 2.7-kb fragment (P(2.7), P(2.5) combined with the 227-bp 5'-untranslated exons) were cloned to produce luciferase constructs. The P(2.5) and the P(2.7) drove luciferase gene expression in the human neuroblastoma cell line SH-SY5Y but not in the human embryonic kidney cell line HEK-293. The 5'-untranslated exons could greatly enhance gene expression in SH-SY5Y cells. The P(2.7) could be used as a functional unit to study the role of SCN1A noncoding sequences in gene expression. These findings will also help in exploring the possibility of promoter mutant-induced diseases and revealing the mechanism underlying the regulation of SCN1A expression in the normal brain.

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Section: Biosoftware Analysesmentioning

confidence: 99%

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confidence: 99%

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Long

Zhao

et al. 2008

J of Neuroscience Research

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“…Some genes contain conserved perfect matches to only one-half of the NRSE. For example, it was recently reported that the SCN8A gene contains a perfect match to the 5Ј-half NRSE, but the flanking sequences, which are also conserved, differ markedly from the NRSE consensus (46). One possibility is that this motif assembles a distinct complex in which REST dimerizes with a different partner.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

Regulation of Tryptophan Hydroxylase-2 Gene Expression by a Bipartite RE-1 Silencer of Transcription/Neuron restrictive Silencing Factor (REST/NRSF) Binding Motif

Patel

Bochar

Turner

et al. 2007

Journal of Biological Chemistry

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Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in raphe serotonin biosynthesis, and polymorphisms of TPH2 are implicated in vulnerability to psychiatric disorders. Dynamic transcription regulation of TPH2 may underlie differences in vulnerability. We identified a transcription element in the TPH2 promoter that resembles the binding motif for RE-1 silencer of transcription (REST; also known as NRSF) transcription factor. REST limits tissue expression of non-neuronal genes through a canonical 21-bp motif called the NRSE (neuron-restrictive silencing element). The NRSE in TPH2 is a novel bipartite variant interrupted by a 6-base insertion. We confirmed that this bipartite NRSE permits transcriptional repression by REST identical to canonical NRSE in rat C6-glioma cells. Synthetic permutations of the motif revealed considerable flexibility in the juxtaposition of the two halves of bipartite NRSE. Computational analysis revealed many bipartite NRSE variants conserved between mouse and human genomes. A subgroup of these was found to bind REST by chromatin immunoprecipitation. Messenger RNAs for TPH2 and potassium channel H6, another gene with a bipartite NRSE, were up-regulated by dominant-negative REST in C6-glioma cells. These findings, which indicate that TPH2 expression is part of the developmental program regulated by REST and suggest that many previously unrecognized genes may be regulated by REST through the novel motif, have implications for the mechanism of REST action.Serotonin levels are regulated by the rate-limiting enzyme tryptophan hydroxylase, of which a neuronal isoform (NCBI Entrez Gene ID: TPH2) 3 was recently identified (1). TPH2 gene expression in the brain is restricted to raphe neurons, and TPH2 is likely the gene coding for the majority of tryptophan hydroxylase in these cells (1, 2). Serotonin modulates a variety of complex behaviors (3), and its signaling is implicated in the mechanism for a subset of antidepressants (4), but its precise role in mood regulation is unclear. A number of manipulations, including restriction of the essential dietary precursor tryptophan (5), stimulant drugs of abuse (6), or adverse developmental experiences (7), result in low brain serotonin levels and may underlie associated depression or anxiety phenotypes. Functional variants of TPH2 in mice are associated with decreased brain serotonin levels (8), and a TPH2 polymorphism in humans arguably (9) confers vulnerability to major depression (10). Associations with TPH2 polymorphisms are also reported for suicide (11), obsessivecompulsive disorder (12), and attention deficit disorder (13)(14)(15).In contrast to the growing number of genetic association studies, little is known about the regulation of TPH2 expression. Limited studies suggest that TPH2 mRNA levels are decreased following stress corticosteroids (16), unchanged (16) or increased by ovarian steroids (17), and increased by hypotensive stress (18) and one recent report suggests that POU3F2 may regulate TPH2 through a functional single-nucleoti...

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“…All transcriptional promoters for the a-subunits of sodium channels described to date have one or two exons 5 0 to the coding sequence and contain TATA-less promoters (Kraner et al, 1998;Kasai et al, 2001;Yang et al, 2004;Drews et al, 2005;Shang and Dudley, 2005;Diss et al, 2008;Long et al, 2008). TATA-less promoters are not privative of sodium channel genes.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterization of the promoter of the mouse sodium‐activated sodium channel Na_x gene (Scn7a)

García-Villegas

López-Álvarez

Arni

et al. 2009

J of Neuroscience Research

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Na(x) is a sodium channel, thought to be a descendant of the voltage-gated sodium channel family. Nevertheless, Na(x) is not activated by voltage but rather by augmentation of extracellular sodium over 150 mM. In the brain, it is localized to the circumventricular organs, important regions for salt and water homeostasis in mammals, where it operates as a sodium-level sensor of body fluid. Na(x) channel is expressed in lung, uterus, and heart, and it is also found in trigeminal and dorsal root ganglia and in nonmyelinating Schwann cells, where its physiological role remains unclarified. Here we identified the promoter and transcription start sites of Na(x) sodium channel in dorsal root ganglia neurons from mouse. We report a characterization of the basal TATA-less promoter and the sequence requirements for promoter activity in Neuro 2A neuroblastoma cells and in dorsal root ganglia neurons, where basal promoter activity seems to require NGFI-C and Ebox DNA elements. Finally, we provide evidence that a repression mechanism that inhibits Na(x) expression may be present in certain tissues. These findings provide the basis with which to understand tissue-specific regulation of Na(x) sodium channel gene (Scn7a) expression.

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Multiple transcripts of sodium channel SCN8A (NaV1.6) with alternative 5′- and 3′-untranslated regions and initial characterization of the SCN8A promoter

Cited by 30 publications

References 50 publications

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Regulation of Tryptophan Hydroxylase-2 Gene Expression by a Bipartite RE-1 Silencer of Transcription/Neuron restrictive Silencing Factor (REST/NRSF) Binding Motif

Identification and functional characterization of the promoter of the mouse sodium‐activated sodium channel Na_x gene (Scn7a)

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Multiple transcripts of sodium channel SCN8A (NaV1.6) with alternative 5′- and 3′-untranslated regions and initial characterization of the SCN8A promoter

Cited by 30 publications

References 50 publications

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Regulation of Tryptophan Hydroxylase-2 Gene Expression by a Bipartite RE-1 Silencer of Transcription/Neuron restrictive Silencing Factor (REST/NRSF) Binding Motif

Identification and functional characterization of the promoter of the mouse sodium‐activated sodium channel Nax gene (Scn7a)

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Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Na_v1.1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons

Identification and functional characterization of the promoter of the mouse sodium‐activated sodium channel Na_x gene (Scn7a)