The histone deacetylase inhibitor trichostatin A induces neurite outgrowth in PC12 cells via the epigenetically regulated expression of the nur77 gene

Tomioka, Takuma; Maruoka, Hiroki; Kawa, Hiromichi; Yamazoe, Ryosuke; Fujiki, Daichi; Shimoke, Koji; Ikeuchi, Toshihiko

doi:10.1016/j.neures.2014.07.009

Cited by 22 publications

(21 citation statements)

References 35 publications

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“…Nr4a1 has been linked to synaptic remodeling, behavioral changes, and dopaminergic loss after administrating MPTP in mice (27). The possible therapeutic role for Nr4a1 has been manifested since neural damage was rescued by Nr4a1 overexpression that decreased cell apoptotic rates (29) and was essential for neuronal differentiation (30). In our study, genes involved in the MAPK pathway ( Fos and Nr4a1 ) were significantly upregulated in the SVZ 3 weeks after MPTP administration.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of the subventricular zone and dentate gyrus in an animal model of Parkinson's disease

Bao

Wang

Zuo

et al. 2017

International Journal of Molecular Medicine

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Adult neurogenesis in the subventricular zone (SVZ), as well as in the subgranular zone contributes to brain maintenance and regeneration. In the adult brain, dopamine (DA) can regulate the endogenous neural stem cells within these two regions, while a DA deficit may affect neurogenesis. Notably, the factors that regulate in vivo neurogenesis in these subregions have not yet been fully characterized, particularly following DA depletion. In thi study, we performed RNA sequencing to investigate transcriptomic changes in the SVZ and dentate gyrus (DG) of mice in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This analysis identified differentially expressed genes which were involved in the regulation of transcription, immune response, extracellular region, cell junction and myelination. These genes partially displayed different temporal profiles of expression, some of which may participate in the metabolic switch related to neurogenesis. Additionally, the mitogen-activated protein kinase (MAPK) signaling pathway was shown to be been positively regulated in the SVZ, while it was negatively affected in the DG following MPTP administration. Overall, our findings indicate that exposure to MPTP may exert different effects on transcriptome profiling between the SVZ and DG.

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Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of the subventricular zone and dentate gyrus in an animal model of Parkinson's disease

Bao

Wang

Zuo

et al. 2017

International Journal of Molecular Medicine

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“…The underlying molecular mechanisms are still unclear although reactivation of specific genes involved in cell fate after epidrug treatments has been identified. For instance, TSA treatment of the PC12 cell line results in increased acetylation of Lys14 on histone H3 and upregulation of the expression of nur77 gene [60]. A neuroprotective effect of HDAC inhibitor (HDACi) treatment mediated by inflammation prevention has been also suggested [61].…”

Section: Main Textmentioning

confidence: 99%

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

et al. 2017

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Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer’s disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

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“…Previous studies have shown that expression of nur77 is significantly increased by db-cAMP in PC12 cells, and that Nur77 is essential for early stage of differentiation in neurons and Schwann cells 20,34,35,44 . To investigate whether the increased expression of Nur77 is mainly responsible for neurite outgrowth that occurs from 0 to 24 hr after 10 µM forskolin treatment, expression of nur77 gene and Nur77 induced by forskolin was examined using qPCR and immunoblotting analysis ( Fig.…”

Section: Resultsmentioning

confidence: 95%

“…CRE sites near the TSS are known to be heavily involved in regulation of transcription. In PC12 cells, we have shown that the CRE site-containing nur77 promoter region near the TSS is associated with acetylated Lys14 of histone H3 after treatment with db-cAMP or HDAC (Histone Deacetylase) inhibitors TSA and K350; and that expression of Nur77 induced by db-cAMP is regulated by the PKA-CREB pathway 20,34,35 . Based on these findings, it is likely that CRE sites upstream of the TSS of nur77 and CREB are important for nur77 expression.…”

Section: Binding Of Creb With Cre Sites Near the Tss Of Nur77 Is Respmentioning

confidence: 99%

Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells

Maruoka

Yamazoe

Takahashi

et al. 2020

Sci Rep

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Forskolin promotes neuronal differentiation of PC12 cells via the PKA-CREB-dependent signaling pathway. Activation of PKA by forskolin phosphorylates CREB, which then binds to CRE sites in numerous gene promoters. However, it is unclear which gene contains the CRE sites responsible for forskolin-induced neuronal differentiation. In this study, we investigated how an immediate early gene, nur77, which has CRE sites in the promoter region, contributes to the early stage of differentiation of forskolin-treated PC12 cells. After treatment with forskolin, expression of Nur77 was upregulated within 1 hr. In addition, knockdown of nur77 inhibited neurite outgrowth induced by forskolin. We also revealed that the specific four CRE sites near the transcriptional start site (TSS) of nur77 were strongly associated with phosphorylated CREB within 1 hr after treatment with forskolin. To analyze the roles of these four sites, reporter assays using the nur77 promoter region were performed. the results showed that nur77 expression was mediated through three of the cRe sites, −242, −222, and −78, and that −78, the nearest of the three to the TSS of nur77, was particularly important. An analysis of neuronal markers controlled by Nur77 after A-CREB-Nur77-Synapsin1 signaling pathway plays a pivotal role in differentiation of forskolin-induced PC12 cells. Low molecular weight natural products may be useful therapeutic agents for neuronal injury 1-6 , and some of these compounds possess neurotrophic and neuroprotective properties 7. Natural products also enhance neurite outgrowth activity of nerve growth factors in experimental models 8 , but the detailed molecular mechanisms underlying the neurotrophic and neuroprotective effects of natural products have not been clearly defined. One such natural product, forskolin, is a cell-permeable diterpenoid extracted from the plant Coleus forskohlii. Forskolin also has blood-brain barrier (BBB) permeability 9. Therefore, forskolin is a potential therapeutic agent for nerve injury, and several studies have shown that forskolin increases the differentiation and survival of dopaminergic neurons in vitro 10-14. Forskolin also induces expression of tyrosine hydroxylase in human fetal brain cortex 15. In addition, forskolin increases the intracellular cAMP level by stimulation of adenylate cyclase, and cAMP-dependent signaling pathways play important roles in neuronal differentiation and neuroplasticity 16,17. Increased cAMP in cells promotes axonal regeneration and neurite outgrowth 18-20 , and it is well-known that cAMP promotes neurite outgrowth by binding to and activating protein kinase A (PKA) 21-23. Activated PKA phosphorylates cAMP response element-binding protein (CREB), which then binds to CRE (cAMP response element) sites in various gene promotor regions 24-26. Some CREB target genes have been identified as immediate early genes (IEGs) that are induced in a CRE-dependent manner. Expression of IEGs can be induced within 1 hr in response to stimuli such as neurotrophin/Trk-or cAMP/PKA-depend...

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The histone deacetylase inhibitor trichostatin A induces neurite outgrowth in PC12 cells via the epigenetically regulated expression of the nur77 gene

Cited by 22 publications

References 35 publications

Transcriptome profiling of the subventricular zone and dentate gyrus in an animal model of Parkinson's disease

Transcriptome profiling of the subventricular zone and dentate gyrus in an animal model of Parkinson's disease

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells

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