Transcriptional Repression of the α7 Nicotinic Acetylcholine Receptor Subunit Gene (CHRNA7) by Activating Protein-2α (AP-2α)

Finlay-Schultz, Jessica; Canastar, Andrew; Short, Margaret N.; Gazzar, Mohamed El; Coughlan, Christina; Leonard, Sherry

doi:10.1074/jbc.m111.276014

Cited by 15 publications

(19 citation statements)

References 75 publications

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“…The present study provides the in vivo results showing that the SVadministration is able to elevate the levels of hippocampal α7nAChR mRNA and protein, but it did not affect the expression of hippocampal α4β2nAChR. A single promoter region on the upstream of transcription start site of α7nAChR subunit gene (CHRNA7) has been found to contain sequences for putative specificity protein family members, AP-2α, and early growth response factor [33]. We observed that the levels of hippocampal AP-2α mRNA and AP-2α protein in SV mice were lower than in control mice.…”

Section: Sv Administration Enhances Expression Of α7nachr Through Redmentioning

confidence: 63%

“…We observed that the levels of hippocampal AP-2α mRNA and AP-2α protein in SV mice were lower than in control mice. AP-2α has been reported to play a negative regulation in CHRNA7 transcription [33]. The supplement of isoprenoid FPP by applying FOH in SV mice could correct the decline of AP-2α level and block the increased expression of α7nAChR, whereas it did not alter the levels of AP-2α and α7nAChR expression in control mice.…”

Section: Sv Administration Enhances Expression Of α7nachr Through Redmentioning

confidence: 91%

“…The results showed that the adminsitration of FOH could abolish the increase in α7nAChR mRNA (P<0.01, n=8) and α7nAChR protein (P<0.01, n=8), and the immune-reactivity of α7nAChR in SV mice, but it did not affect the α7nAChR expression in control mice (P>0.05, n=8). In addition, activating enhancer binding protein 2 alpha (AP-2α) is known to play a negative role in regulating α7nAChR subunit gene (CHRNA7) transcription [33]. The levels of hippocampal AP-2α mRNA (P<0.01, n=8; Fig.…”

Section: Effects Of Sv Administration On Hippocampal α7nachr Expressionmentioning

confidence: 99%

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Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor

et al. 2015

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Simvastatin (SV) has been reported to improve cognitive deficits in Alzheimer's disease. Here, we show that chronic administration of SV (20 mg/kg) for 30 days in adult mice (SV mice) enhanced spatial cognitive performance as assessed by Morris water maze and Y-maze. To explore mechanisms underlying SV-enhanced spatial cognition, we further examined synaptic properties and long-term potentiation (LTP) in hippocampal CA1, hippocampal α7nAChR expression, and Akt and ERK2 phosphorylation. In comparison with controls, the SV administration caused increase in presynaptic glutamate release and amplitude of NMDAr-dependent LTP (LTP-augmentation), and decrease in threshold of NMDAr-independent LTP induction (LTP-facilitation). The supplement of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the spatial cognitive potentiation, increased glutamate release, and LTP-augmentation/facilitation in SV mice. Expression of α7nAChR, but not α4β2nAChR, was increased in hippocampal pyramidal cells of SV mice with the reduction of transcription factor AP-2α, which were abolished by FOH. Levels of Akt and ERK2 phosphorylation in SV mice were elevated, which were suppressed by FOH or α7nAChR antagonist methyl-lycaconitine (MLA). In hippocampal slices obtained from SV mice, acute perfusion of MLA blocked the increased glutamate release, whereas FOH, PI3K inhibitor LY294002, or MEK inhibitor U0126 could not. In the slices of SV mice, the perfusion of MLA or U0126, but not FOH, abolished the LTP-augmentation and LTP-facilitation. By contrast, LY294002 prevented the LTP-facilitation but failed to affect the LTP-augmentation. The findings indicate that the administration of SV through reducing FPP increases α7nAChR expression and α7nAChR-related Akt and ERK2 phosphorylation, leading to LTP enhancement and spatial cognitive potentiation.

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Section: Sv Administration Enhances Expression Of α7nachr Through Redmentioning

confidence: 63%

Section: Sv Administration Enhances Expression Of α7nachr Through Redmentioning

confidence: 91%

Section: Effects Of Sv Administration On Hippocampal α7nachr Expressionmentioning

confidence: 99%

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Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor

et al. 2015

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“…The AP2-α gene has been identified as a potent repressor of CHRNA7 transcription (Finlay-Schultz et al, 2011). AP-2α is a transcription factor that binds in the proximal promoter of CHRNA7 .…”

Section: The Alpha7 Nicotinic Acetylcholine Receptor Gene Chrna7mentioning

confidence: 99%

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

et al. 2015

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The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer’s disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease.

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“…For the other genes that we detect, Hek et al [43] reports that SNP rs161645 near NUDT12 is associated with depressive symptoms; NRN1L expresses predominantly in the nervous system [44] and may play a role in psychiatric diseases [45]; and STRA13 may have an effect on SCZ by influencing gene CHRNA7 [46].…”

Section: Real Data Applicationmentioning

confidence: 80%

Adaptive Fisher method detects dense and sparse signals in association analysis of SNV sets

et al. 2020

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Background: With the development of next generation sequencing (NGS) technology and genotype imputation methods, statistical methods have been proposed to test a set of genomic variants together to detect if any of them is associated with the phenotype or disease. In practice, within the set, there is an unknown proportion of variants truly causal or associated with the disease. There is a demand for statistical methods with high power in both dense and sparse scenarios, where the proportion of causal or associated variants is large or small respectively. Results: We propose a new association test-weighted Adaptive Fisher (wAF) that can adapt to both dense and sparse scenarios by adding weights to the Adaptive Fisher (AF) method we developed before. Using simulation, we show that wAF enjoys comparable or better power to popular methods such as sequence kernel association tests (SKAT and SKAT-O) and adaptive SPU (aSPU) test. We apply wAF to a publicly available schizophrenia dataset, and successfully detect thirteen genes. Among them, three genes are supported by existing literature; six are plausible as they either relate to other neurological diseases or have relevant biological functions. Conclusions: The proposed wAF method is a powerful disease-variants association test in both dense and sparse scenarios. Both simulation studies and real data analysis indicate the potential of wAF for new biological findings.

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Transcriptional Repression of the α7 Nicotinic Acetylcholine Receptor Subunit Gene (CHRNA7) by Activating Protein-2α (AP-2α)

Cited by 15 publications

References 75 publications

Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor

Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

Adaptive Fisher method detects dense and sparse signals in association analysis of SNV sets

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