Differential Expression of Multiple Disease-Related Protein Groups Induced by Valproic Acid in Human SH-SY5Y Neuroblastoma Cells

Hu, Tsung‐Ming; Chung, Hsiang-Sheng; Ping, Lieh-Yung; Hsu, Shih-Hsin; Tsai, Hsin-Yao; Chen, Shaw-Ji; Cheng, Min-Chih

doi:10.3390/brainsci10080545

Cited by 6 publications

(3 citation statements)

References 60 publications

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“…SMARCA-deficiencies are associated to several malignancies and birth defects; its homozygous loss lead to embryo lethality (Pulice and Kadoch, 2016). Valproic acid is known to alter the expression of SMARCA4 and SMARCD1 in neuroblastoma cells (Hu et al, 2020), and SMARCA genes are suggested as members of the neurogenic transcriptional network control (Higgins et al, 2019). Hence, valproate-induced perturbances in SMARCA genes might be sufficiently disruptive to explain Fetal Valproate Syndrome.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

et al. 2020

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Embryofetal development is a critical process that needs a strict epigenetic control, however, perturbations in this balance might lead to the occurrence of congenital anomalies. It is known that anticonvulsants potentially affect epigenetics-related genes, however, it is not comprehended whether this unbalance could explain the anticonvulsants-induced fetal syndromes. In the present study, we aimed to evaluate the expression of epigenetics-related genes in valproic acid, carbamazepine, or phenytoin exposure. We selected these three anticonvulsants exposure assays, which used murine or human embryonic stem-cells and were publicly available in genomic databases. We performed a differential gene expression (DGE) and weighted gene co-expression network analysis (WGCNA), focusing on epigenetics-related genes. Few epigenetics genes were differentially expressed in the anticonvulsants’ exposure, however, the WGCNA strategy demonstrated a high enrichment of chromatin remodeling genes for the three drugs. We also identified an association of 46 genes related to Fetal Valproate Syndrome, containing SMARCA2 and SMARCA4, and nine genes to Fetal Hydantoin Syndrome, including PAX6, NEUROD1, and TSHZ1. The evaluation of stem-cells under drug exposure can bring many insights to understand the drug-induced damage to the embryofetal development. The candidate genes here presented are potential biomarkers that could help in future strategies for the prevention of congenital anomalies.

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Section: Discussionmentioning

confidence: 99%

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

et al. 2020

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“… 112 In BD, studies have shown that E2 and E3 may be involved in the pathophysiology of the disorder. 113 , 114 UBE3A and CUL1 genes (coding for E3) are negatively expressed in the frontal cortex of BD subjects. 114 Valproic acid, frequently used as an antimanic agent in BD can induce differential expression of ANAPC4, CDC23, FBXO2, FBXO4, NEDD4, TRAF6, UBE2D1, UBE2E1, UBE2E3 and UBE2G2 , genes encoding E2 and E3 113 in human neuroblastoma cells.…”

Section: Ubiquitin and Proteasome System Dysfunction In Mood Disordersmentioning

confidence: 98%

Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article

Santos¹,

Campos²,

Nascimento³

2023

NDT

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Mood disorders are disabling conditions that cause significant functional impairment. Due to the clinical heterogeneity and complex nature of these disorders, diagnostic and treatment strategies face challenges. The etiology of mood disorders is multifactorial, involving genetic and environmental aspects that are associated with specific biological pathways including inflammation, oxidative stress, and neuroprotection. Alterations in these pathways may reduce the cell’s ability to recover from stress conditions occurring during mood episodes. The endo-lysosomal and autophagy pathway (ELAP) and the ubiquitin-proteasome system (UPS) play critical roles in protein homeostasis, impacting neuroplasticity and neurodevelopment. Thus, emerging evidence has suggested a role for these pathways in mental disorders. In the case of neurodegenerative diseases (NDDs), a deeper understanding in the role of ELAP and UPS has been critical to discover new treatment targets. Since it is suggested that NDDs and mood disorders share clinical symptomatology and risk factors, it has been hypothesized that there might be common underlying molecular pathways. Here, we review the importance of the ELAP and UPS for the central nervous system and for mood disorders. Finally, we discuss potential translational strategies for the diagnosis and treatment of major depressive disorder and bipolar disorder associated with these pathways.

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“…An enrichment analysis of gene-disease associations was performed using the DisGeNET database [54]. RT-qPCR assays were performed using the comparative ∆∆Ct method to validate the differential gene expression [55]. The expression levels of GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIA2, GRIA4, GABRB3, GRM8, and KCNJ3 were assayed using the QuantStudio 3 real-time PCR system in combination with continuous SYBR Green detection (ThermoFisher Scientific Inc.).…”

Section: Human Cell Line Identificationmentioning

confidence: 99%

Transcriptomic Investigation in CRISPR/Cas9-Mediated GRIK1-, GRIK2-, and GRIK4-Gene-Knockout Human Neuroblastoma Cells

Hu,

Hsu,

Tsai

et al. 2024

SynBio

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The glutamate ionotropic kainate receptors, encoded by the GRIK gene family, are composed of four subunits and function as ligand-activated ion channels. They play a critical role in regulating synaptic transmission and various synaptic receptors’ processes, as well as in the pathophysiology of schizophrenia. However, their functions and mechanisms of action need to be better understood and are worthy of exploration. To further understand the exact role of the kainate receptors in vitro, we generated kainate-receptor-knockout (KO) isogenic SH-SY5Y cell lines using the CRISPR/Cas9-mediated gene editing method. We conducted RNA sequencing (RNA-seq) to determine the differentially expressed genes (DEGs) in the isogenic edited cells and used rhodamine-phalloidin staining to quantitate filamentous actin (F-actin) in differentiated edited cells. The RNA-seq and the Gene Ontology enrichment analysis revealed that the genetic deletion of the GRIK1, GRIK2, and GRIK4 genes disturbed multiple genes involved in numerous signal pathways, including a converging pathway related to the synaptic membrane. An enrichment analysis of gene–disease associations indicated that DEGs in the edited cell lines were associated with several neuropsychiatric disorders, especially schizophrenia. In the morphology study, fluorescent images show that less F-actin was expressed in differentiated SH-SY5Y cells with GRIK1, GRIK2, or GRIK4 deficiency than wild-type cells. Our data indicate that kainate receptor deficiency might disturb synaptic-membrane-associated genes, and elucidating these genes should shed some light on the pathophysiology of schizophrenia. Furthermore, the transcriptomic profiles for kainate receptor deficiency of SH-SY5Y cells contribute to emerging evidence for the novel mechanisms underlying the effect of kainate receptors and the pathophysiology of schizophrenia. In addition, our data suggest that kainate-receptor-mediated F-actin remodeling may be a candidate mechanism underlying schizophrenia.

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Differential Expression of Multiple Disease-Related Protein Groups Induced by Valproic Acid in Human SH-SY5Y Neuroblastoma Cells

Cited by 6 publications

References 60 publications

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article

Transcriptomic Investigation in CRISPR/Cas9-Mediated GRIK1-, GRIK2-, and GRIK4-Gene-Knockout Human Neuroblastoma Cells

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