Valproic acid exposure leads to upregulation and increased promoter histone acetylation of sepiapterin reductase in a serotonergic cell line

Balasubramanian, Diana; Deng, Alicia X.; Doudney, Kit; Hampton, Mark B.; Kennedy, Martin A.

doi:10.1016/j.neuropharm.2015.06.018

Cited by 26 publications

(27 citation statements)

References 84 publications

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“…The hyperacetylated regions I and IV within the DAT promoter may be more promising in identifying additional transcription factors and other markers involved in the regulation of DAT. Although valproate has been observed to induce DNA demethylation in some promoters (Manev and Uz, 2002; Tremolizzo et al, 2002), others have not observed this effect (Balasubramanian et al, 2015). Further, the DAT promoter is highly unmethylated (over 95%) in rat primary neurons (He et al, 2011) and we found no significant effect of DNA methyltransferase inhibitors (RG108 and 5-aza-2-deoxycytidine) on DAT expression in SK-N-AS cells (Green et al, 2015) or in N27 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

et al. 2017

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The dopamine transporter (DAT) is the key regulator of dopaminergic transmission and is a target of several xenobiotics, including pesticides and pharmacological agents. Previously, we identified a prominent role for histone deacetylases in the regulation of DAT expression. Here, we utilized a rat dopaminergic cell line (N27) to probe the responsiveness of DAT mRNA expression to inhibitors of histone acetylation. Inhibition of histone deacetylases (HDACs) by valproate, butyrate and Trichostatin A led to a 3 to 10-fold increase in DAT mRNA expression, a 50% increase in protein levels, which were accompanied by increased H3 acetylation levels. To confirm the mechanism of valproate-mediated increase in DAT mRNA, chromatin immunoprecipitation (ChIP) assays were used and demonstrated a significant increase in enrichment of acetylation of histone 3 on lysines 9 and 14 (H3K9/K14ac) in the DAT promoter. Expression of Nurr1 and Pitx3, key regulators of DAT expression, were increased following valproate treatment and Nurr1 binding was enriched in the DAT promoter. Together, these results indicate that histone acetylation and subsequent enhancement of transcription factor binding are plausible mechanisms for DAT regulation by valproate and, perhaps, by other xenobiotics.

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Section: Discussionmentioning

confidence: 99%

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

et al. 2017

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“…Before treatment with drugs, the cells were seeded in six-well plates (3.5 cm 2 ) with 3.5 × 10 4 cells for each well and incubated overnight. The cells were then respectively treated with VPA (titrated from 0 to 2 mM), lamotrigine (LTG, titrated from 0 to 100 μM), and carbamazepine (CBZ, titrated from 0 to 100 μM) according to a previous study [47]. All these drugs were purchased from Sigma-Aldrich.…”

Section: Cell Culture and Drug Treatmentmentioning

confidence: 99%

“…Three widely used antiepileptic drugs sodium VPA, CBZ, and LTG were used to examine their effects on Scn3a expression in mouse Neuro-2a cells at the doses according to previous studies [47,49]. After treated with these drugs at a dose titration for 72 h, a significant decrease in Scn3a mRNA levels was observed in the cells treated with VPA at the dose of 0.5 and 1 mM, but no alteration at the dose of 1.5 and 2 mM (Fig.…”

Section: Vpa Decreases Scn3a Mrna Expression and Protein Levels In Cumentioning

confidence: 99%

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

et al. 2016

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Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of Scn3a expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate Scn3a expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in Scn3a promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased Scn3a expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Na1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of Scn3a and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of Scn3a expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.

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“…Previous immunohistochemical evidence also suggests that serotonergic fibers have dense terminals in the basolateral complex of the amygdala . In addition, HDACi such as valproic acid (VPA) and trichostatin A (TSA) modulate the activity of serotonergic neurons . Growing evidences also suggest that HDACi ameliorated deficits in synaptic plasticity, cognition, and stress‐related behaviors in a wide range of neurologic and psychiatric disorders including AD, anxiety, and mood disorders .…”

Section: Discussionmentioning

confidence: 99%

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25‐35‐induced anxiety and cognitive deficits in a mouse model

Huang

Hsieh-Li

2018

CNS Neurosci Ther

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Summary Aims Recently, histone deacetylase ( HDAC ) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease ( AD ). However, HDAC i treatments exhibit diverse functions with unfavorable effects in AD . Thus, the development of selective HDAC i without side effects is urgently needed. Methods HDAC i, namely, BML 210, MGCD 0103, PXD 101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ 25‐35 (50 μmol/L). MGCD 0103 was chosen for in vivo tests and was intraperitoneally injected into C57 BL /6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA 1 injection of oligomeric Aβ 25‐35 . Brain samples were collected for pathological analyses after the behavioral analyses including open‐ field test ( OFT ), elevated plus maze ( EPM ), Y‐maze, and Morris water maze ( MWM ). Results Among the HDAC i, MGCD 0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD 0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD 0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α‐tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD 0103 treatment did not show liver or kidney toxicity in mice. Conclusions These results reveal MGCD 0103 could be a potential therapeutic agent against AD .

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Valproic acid exposure leads to upregulation and increased promoter histone acetylation of sepiapterin reductase in a serotonergic cell line

Cited by 26 publications

References 84 publications

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25‐35‐induced anxiety and cognitive deficits in a mouse model

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Valproic acid exposure leads to upregulation and increased promoter histone acetylation of sepiapterin reductase in a serotonergic cell line

Cited by 26 publications

References 84 publications

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ25‐35‐induced anxiety and cognitive deficits in a mouse model

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MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25‐35‐induced anxiety and cognitive deficits in a mouse model