Epigenetic Induction of EGR-1 Expression by the Amyloid Precursor Protein during Exposure to Novelty

Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Brion, Jean Pierre; Kienlen‐Campard, Pascal; Smet, Charles De; Octave, Jean Noël

doi:10.1371/journal.pone.0074305

Cited by 24 publications

(28 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In Tg2576 and APP751SL mice, characterized by overexpression of hAPP, hippocampal Egr1 was significantly decreased relative to WT controls after MWM training, in which mice were impaired on learning and memory phases. These data are in agreement with studies documenting epigenetic downregulation of Egr1 in neurons by APP (Hendrickx et al, 2013), a process that has shown to be mediated by CREB (Hendrickx et al, 2014), as overexpression of hAPP would be expected to further suppress Egr1 to a pathological degree. Studies thus far, however, have not investigated the relationship between amyloidogenic processes, Egr1 and tau pathology or how NF-κB alterations potentially link these changes in an AD model in which NFTs occur (e.g., 3xTg strain).…”

Section: Early Growth Response (Egr) Factorssupporting

confidence: 92%

“…In a recent microarray study focusing on the CA1 hippocampal subfield, Egr1 was deemed a central regulator of genes implicated in AD (Acquaah-Mensah and Taylor, 2016). Post-mortem studies consistently confirm upregulation of Egr1 in both the cortex (Shim et al, 2003; Lu et al, 2011; Hendrickx et al, 2013) and hippocampus (MacGibbon et al, 1997; Gómez Ravetti et al, 2010; Lu et al, 2011). Further, Egr1 and tau were colocalized in the AD hippocampus (MacGibbon et al, 1997).…”

Section: Early Growth Response (Egr) Factorsmentioning

confidence: 87%

“…BDNF is regulated by neural activity (Lu et al, 2013) and is also a target of key transcriptional regulators in neurons, including CREB (Tao et al, 1998) and NF-κB (Marini et al, 2004), whose activation elevates BDNF expression (Lipsky et al, 2001). Egr1 has also been shown to bind to BDNF, resulting in decreased expression in neural tissue (Hendrickx et al, 2013). …”

Section: Bdnfmentioning

confidence: 99%

See 2 more Smart Citations

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

View full text Add to dashboard Cite

Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

show abstract

Section: Early Growth Response (Egr) Factorssupporting

confidence: 92%

Section: Early Growth Response (Egr) Factorsmentioning

confidence: 87%

Section: Bdnfmentioning

confidence: 99%

See 1 more Smart Citation

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

View full text Add to dashboard Cite

show abstract

“…We have previously demonstrated that trichostatin A, a specific HDAC inhibitor, was able to induce Egr1 gene transcription in both APP+/+ and APP−/− neurons, although induction was significantly higher in APP−/− neurons, in agreement with higher H4 acetylation at the Egr1 gene promoter in these cells [20].…”

Section: Discussionmentioning

confidence: 63%

Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

et al. 2014

Self Cite

View full text Add to dashboard Cite

We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP−/−), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf and Arc. Down regulation of Egr1, c-Fos and Bdnf transcription resulted from a decreased enrichment of acetylated histone H4 on the corresponding gene promoter. Further characterization of H4 acetylation at Egr1 and c-Fos promoters revealed increased acetylation of H4K5 and H4K12 residues in APP−/− mice. Whereas APP affected Egr1 promoter activity by reducing access of the CREB transcription factor, its effect on c-Fos appeared to depend on increased recruitment of HDAC2 histone deacetylase to the gene promoter. The physiological relevance of the epigenetic regulation of Egr1 and c-Fos gene transcription by APP was further analyzed following exposure of mice to novelty. Although transcription of Egr1 and c-Fos was increased following exposure of APP+/+ mice to novelty, such an induction was not possible in APP−/− mice with a high basal level of expression of these immediate early genes. Altogether, these results demonstrate that APP-mediated regulation of c-Fos and Egr1 by different epigenetic mechanisms is needed for their induction during exposure to novelty.

show abstract

“…Hendrickx et al reported that transcription of the Egr-1 gene to be regulated by APP. In primary cultures of cortical neurons, APP significantly down regulation Egr-1 expression at both mRNA and protein levels in a γ-secretase independent manner and that APP fosters a low level of Egr-1 and c-fos expression in the mouse prefrontal cortex by inhibiting CREB recruitment and improving HDAC2 recruitment to the corresponding gene promoters [33,34]. Koldamova The results demonstrated that Purα overexpression can suppress endogenous Egr-1 expression and that p53 can induce endogenous Egr-1 expression also, whereas mutant p53 cannot yield this result.…”

Section: Figurementioning

confidence: 93%

Interplay between Pur? and Egr-1 in the Transcriptional Regula-tion of Amyloid Precursor Protein Gene Expression

Chai¹,

Li²,

Guo³

et al. 2015

Ann Clin Lab Res

View full text Add to dashboard Cite

Background: One of the pathological hallmarks of Alzheimer's disease is the presence of fibrillary amyloid-β deposits, which result from cleavage of the amyloid precursor protein. Understanding the regulatory mechanism of the amyloid precursor protein gene expression is crucial for comprehending the genesis and development of Alzheimer's disease. The nucleic acid binding protein, Purα, is best characterized as a transcriptional factor (TF) with affinity to singlestrand G/C-rich regions. In a previous study, we demonstrated that the Purα protein can downregulate amyloid precursor protein (APP) promoter activity, but the mechanism underlying this downregulation requires further investigation. To better understand this mechanism, we analyzed the characteristic of the APP promoter and found that another transcriptional factor, namely Egr-1, can bind the APP promoter and may exert transcriptional regulatory effects on APP gene expression. Therefore, the interaction between these two transcriptional factors may explain the mechanism in regulating APP gene expression.

show abstract

Epigenetic Induction of EGR-1 Expression by the Amyloid Precursor Protein during Exposure to Novelty

Cited by 24 publications

References 36 publications

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

Interplay between Pur? and Egr-1 in the Transcriptional Regula-tion of Amyloid Precursor Protein Gene Expression

Contact Info

Product

Resources

About