Neuron-restrictive Silencer Factor (NRSF) Represses Cocaine- and Amphetamine-regulated Transcript (CART) Transcription and Antagonizes cAMP-response Element-binding Protein Signaling through a Dual NRSE Mechanism

Zhang, Jing; Wang, Sihan; Lin, Yuan; Yang, Yinxiang; Zhang, Bowen; Liu, Qingbin; Chen, Lin; Yue, Wen; Li, Yanhua; Pei, Xuetao

doi:10.1074/jbc.m112.376590

Cited by 13 publications

(9 citation statements)

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“…Similarly, CART-mediated ERK signaling mitigated cortical neuronal demise in response to Aβ toxicity 6 . Further mechanistic examinations have indicated that ischemia-induced suppression of CART expression was modulated by the transcriptional repressor known as neuron-restrictive silencer element 10 . In addition, it has been proposed that attenuation of dopaminergic neuronal cell loss after CART treatment in MPTP-treated mice could be attributed to the anti-oxidative properties of CART 7 .…”

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confidence: 99%

CART treatment improves memory and synaptic structure in APP/PS1 mice

Jin

Liou

Shi

et al. 2015

Sci Rep

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Major characteristics of Alzheimer’s disease (AD) include deposits of β-amyloid (Aβ) peptide in the brain, loss of synapses, and cognitive dysfunction. Cocaine- and amphetamine-regulated transcript (CART) has recently been reported to attenuate Aβ-induced toxicity. In this study, CART localization in APP/PS1 mice was characterized and the protective effects of exogenous CART treatment were examined. Compared to age-matched wild type mice, 8-month-old APP/PS1 mice had significantly greater CART immunoreactivity in the hippocampus and cortex. A strikingly similar pattern of Aβ plaque-associated CART immunoreactivity was observed in the cortex of AD cases. Treatment of APP/PS1 mice with exogenous CART ameliorated memory deficits; this effect was associated with improvements in synaptic ultrastructure and long-term potentiation, but not a reduction of the Aβ plaques. Exogenous CART treatment in APP/PS1 mice prevented depolarization of the mitochondrial membrane and stimulated mitochondrial complex I and II activities, resulting in an increase in ATP levels. CART treatment of APP/PS1 mice also reduced reactive oxygen species and 4-hydroxynonenal, and mitigated oxidative DNA damage. In summary, CART treatment reduced multiple neuropathological measures and improved memory in APP/PS1 mice, and may therefore be a promising and novel therapy for AD.

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confidence: 99%

CART treatment improves memory and synaptic structure in APP/PS1 mice

Jin

Liou

Shi

et al. 2015

Sci Rep

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“…Many of the down-regulated DEGs are involved in neurodevelopment by promoting neurite or axon outgrowth, including SEMA3E [53], NTNG1 [54], and CARTPT , which is also involved in stress responses and sensory processing (Fig. 3b) [55]. Additional down-regulated DEGs such as SLIT2 [56] and UNC5D [57] have been shown to function as repulsive neuronal and axon guidance molecules (Fig.…”

Section: Resultsmentioning

confidence: 99%

Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development

et al. 2016

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BackgroundIron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency.ResultsIn total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function.ConclusionsNeonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive development in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3216-y) contains supplementary material, which is available to authorized users.

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“…Subsequent studies revealed that REST induction by ischemia, had more pronounced effects on gene expression, leading to the epigenetic remodeling and suppression of several neuronal genes, which ultimately lead to cell death 53 . Studies using cultured neuroblastoma cell lines, subjected to an in vitro model of ischemia, oxygen and glucose deprivation, also exhibited increased REST mRNA and protein 58 . These studies were the first to identify a potential link between low oxygen and REST regulation ( Table 2).…”

Section: 1-the Repressor Element 1-silencing Transcription Factor (mentioning

confidence: 97%

“…REST is overexpressed in neuronal cancers, and has oncogeneic properties, it inhibits apoptosis and promotes tumorigenisis 74,75 . Interestingly, hypoxic neuroblastoma tumors and cells exposed to hypoxia (1% oxygen) down-regulate neuronal markers 78,79 , and REST protein is induced in oxygen/glucose deprived SK-N-SH neuroblastoma cells 58 . Thus, it is plausible that REST induction by the hypoxic microenvironment known to be present in neuronal tumours 80 , contributes to its oncogenic role.…”

Section: 21-physiological Relevance Of Rest Regulation By Hypoxiamentioning

confidence: 98%

The regulation of transcriptional repression in hypoxia

Cavadas

Cheong

Taylor

2017

Experimental Cell Research

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A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element-1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.

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Neuron-restrictive Silencer Factor (NRSF) Represses Cocaine- and Amphetamine-regulated Transcript (CART) Transcription and Antagonizes cAMP-response Element-binding Protein Signaling through a Dual NRSE Mechanism

Cited by 13 publications

References 46 publications

CART treatment improves memory and synaptic structure in APP/PS1 mice

CART treatment improves memory and synaptic structure in APP/PS1 mice

Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development

The regulation of transcriptional repression in hypoxia

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