Regulation of <scp>DNA</scp> methylation by ethanol induces tissue plasminogen activator expression in astrocytes

Zhang, Xiaolu; Kusumo, Handojo; Sakharkar, Amul J.; Pandey, Subhash C.; Guizzetti, Marina

doi:10.1111/jnc.12465

Cited by 47 publications

(54 citation statements)

References 35 publications

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“…DNMT1, DNMT3a and DNMT3b by siRNA treatment leads to increases in other two isoforms (Kundakovic et al, 2009). Recently, we reported that DNMT activity and DNMT3a protein expression in cultured astrocytes was attenuated by ethanol (Zhang et al, 2013). LaPlant et al (2010) found that DNMT3a expression was up-regulated in the nucleus accumbens by chronic cocaine use and chronic social stress, suggesting an important role for DNMT3a in regulating emotional behavior and spine plasticity.…”

Section: Discussionmentioning

confidence: 99%

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Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats

Sakharkar¹,

Tang²,

Zhang³

et al. 2014

Int. J. Neuropsychopharm.

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Epigenetic mechanisms appear to play an important role in neurodevelopment. We investigated the effects of acute ethanol exposure on anxiety measures and function of histone deacetylases (HDAC) and DNA methyltransferases (DNMT) in the amygdala and bed nucleus of stria terminalis (BNST) of adolescent rats. One hour after ethanol exposure, rats were subjected to anxiety measures. A subset of adolescent rats was exposed to two doses (24 hrs apart) of ethanol (2 g/kg) to measure rapid ethanol tolerance to anxiolysis. The HDAC and DNMT activities and mRNA levels of DNMT isoforms were measured in the amygdala and BNST. The lower dose of ethanol (1 g/kg) produced neither anxiolysis, nor inhibited the HDAC and DNMT activities in the amygdala and BNST, except DNMT activity in BNST was attenuated. Anxiolysis by ethanol was observed at 2 and 2.25 g/kg, whereas higher doses (2.5 and 3 g/kg) were found to be sedative. DNMT activity in the amygdala and BNST, and nuclear HDAC activity in the amygdala, but not in the BNST were also inhibited by these doses of ethanol. A lack of tolerance was observed on ethanol-induced inhibition of DNMT activity in the amygdala and BNST, and nuclear HDAC activity in the amygdala, as well to anxiolysis produced by ethanol (2 g/kg). The DNMT1, DNMT3a, and DNMT3b mRNA expression in the amygdala was not affected by either one or two doses of 2 g/kg. However, DNMT1 and DNMT3a expression in the BNST was increased whereas DNMT3l mRNA was decreased in the amygdala after two doses of 2 g/kg ethanol. These results suggest that reduced sensitivity to anxiolysis and the lack of rapid tolerance to the anxiolytic effects of ethanol and inhibition of HDAC and DNMT functions may play a role in engaging adolescents in binge drinking patterns.

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Section: Discussionmentioning

confidence: 99%

“…DNMT activity in amygdala and BNST tissues was measured using the EpiQuik ™ DNA methyltransferases activity/inhibition assay kit (Epigentek; Brooklyn, NY), as described by us previously (Zhang et al, 2013). Nuclear fractions of the tissue lysates were prepared using a nuclear extraction kit (Sigma, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats

Sakharkar¹,

Tang²,

Zhang³

et al. 2014

Int. J. Neuropsychopharm.

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“…In this regard, modulation in neuronal functions mediated by epigenomic changes, which cause alteration in chromatin architecture without affecting the nucleotide sequence arrangements in DNA, have been identified as one of the major risk factors in several psychiatric illnesses including depression and suicidal behavior (Haghighi et al, 2014; Higuchi et al, 2011; Keller et al, 2010; Maussion et al, 2014; Numata et al, 2015; Zhang et al, 2014; Zhang et al, 2015). Interestingly, in suicidal patients, a few studies show that these epigenetic modifications can be independent of psychiatric illnesses such as depression (Kang et al, 2013; Kim et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation

Roy

Shelton

Dwivedi

2017

Journal of Psychiatric Research

114

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Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n=20), MDD patients with (n=14) or without serious suicidal ideation (n=10), we studied methylation of the stress-associated genes Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1) . In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.

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“…Ethanol exposure affects DNA methylation in glia and increases tissue plasminogen activator (tPA) expression, which is involved in the inhibition of neuritogenesis and regulates neuronal plasticity (Zhang, Kusumo, Sakharkar, Pandey, & Guizzetti, 2014). Additionally, amygdaloid tPA has been implicated in regulating stress responses during acute cocaine withdrawal (Zhou, Maiya, Norris, Kreek, & Strickland, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Epigenetic Landscape of Alcoholism

Krishnan

Sakharkar

Teppen

et al. 2014

International Review of Neurobiology

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Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure, but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, holds great therapeutic potential in the treatment and prevention of alcoholism.

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Regulation of DNA methylation by ethanol induces tissue plasminogen activator expression in astrocytes

Cited by 47 publications

References 35 publications

Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats

Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats

DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation

The Epigenetic Landscape of Alcoholism

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