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Epigenetics-beyond the genome in alcoholism.

Starkman BG, Sakharkar AJ, Pandey SC - Alcohol Res (2012)

Bottom Line: Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence.The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction.Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois.

ABSTRACT
Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism.

No MeSH data available.


Related in: MedlinePlus

A schematic diagram depicting possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to rapid tolerance to the anxiolytic effects of ethanol. Acute ethanol exposure can inhibit both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities (Pandey et al. 2008a). This inhibition correlates with increased amygdaloid levels of CREB-binding protein (CBP), which has histone acetyltransferase (HAT) activity. The observed changes in HDAC activity and CBP levels also correlate with increased histone acetylation (H3-K9 and H4-K8) in the central and medial nucleus of amygdala, resulting in a relaxed chromatin structure. As a result, the transcriptional machinery can more easily access the DNA, leading to increased gene expression. Increased amygdaloid expression of certain genes, such as neuropeptide Y or brain-derived neurotrophic factor, may mediate the anxiolytic effects of acute ethanol exposure (Pandey et al. 2008a, b). Cellular tolerance at the level of HDAC-induced chromatin remodeling in the amygdala may be operative in rapid tolerance to the anxiolytic effects of ethanol (Sakharkar et al. 2012).NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; Ac = acetylation site.
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f4-arcr-34-3-293: A schematic diagram depicting possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to rapid tolerance to the anxiolytic effects of ethanol. Acute ethanol exposure can inhibit both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities (Pandey et al. 2008a). This inhibition correlates with increased amygdaloid levels of CREB-binding protein (CBP), which has histone acetyltransferase (HAT) activity. The observed changes in HDAC activity and CBP levels also correlate with increased histone acetylation (H3-K9 and H4-K8) in the central and medial nucleus of amygdala, resulting in a relaxed chromatin structure. As a result, the transcriptional machinery can more easily access the DNA, leading to increased gene expression. Increased amygdaloid expression of certain genes, such as neuropeptide Y or brain-derived neurotrophic factor, may mediate the anxiolytic effects of acute ethanol exposure (Pandey et al. 2008a, b). Cellular tolerance at the level of HDAC-induced chromatin remodeling in the amygdala may be operative in rapid tolerance to the anxiolytic effects of ethanol (Sakharkar et al. 2012).NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; Ac = acetylation site.

Mentions: Correction of deficits in CBP function increasingly has become an important target in the treatment of neurological disorders, including Rubinstein-Taybi syndrome (RSTS), Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (Klevytska et al. 2010; Rouaux et al. 2004; Selvi et al. 2010). Mutations in the CBP gene are prevalent in RSTS (Alarcon et al. 2004; Bartsch et al. 2005; Roelfsema et al. 2005). For example, exon deletions in the genes that encode p300 and CBP have been detected in children with RSTS (Tsai et al. 2011). The changes in CBP function described in these neurological disorders are similar to neuroadaptations observed in alcoholism; therefore, CBP–HAT may be an important factor in the development of alcoholism (see figures 4 and 5).


Epigenetics-beyond the genome in alcoholism.

Starkman BG, Sakharkar AJ, Pandey SC - Alcohol Res (2012)

A schematic diagram depicting possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to rapid tolerance to the anxiolytic effects of ethanol. Acute ethanol exposure can inhibit both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities (Pandey et al. 2008a). This inhibition correlates with increased amygdaloid levels of CREB-binding protein (CBP), which has histone acetyltransferase (HAT) activity. The observed changes in HDAC activity and CBP levels also correlate with increased histone acetylation (H3-K9 and H4-K8) in the central and medial nucleus of amygdala, resulting in a relaxed chromatin structure. As a result, the transcriptional machinery can more easily access the DNA, leading to increased gene expression. Increased amygdaloid expression of certain genes, such as neuropeptide Y or brain-derived neurotrophic factor, may mediate the anxiolytic effects of acute ethanol exposure (Pandey et al. 2008a, b). Cellular tolerance at the level of HDAC-induced chromatin remodeling in the amygdala may be operative in rapid tolerance to the anxiolytic effects of ethanol (Sakharkar et al. 2012).NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; Ac = acetylation site.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860414&req=5

f4-arcr-34-3-293: A schematic diagram depicting possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to rapid tolerance to the anxiolytic effects of ethanol. Acute ethanol exposure can inhibit both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities (Pandey et al. 2008a). This inhibition correlates with increased amygdaloid levels of CREB-binding protein (CBP), which has histone acetyltransferase (HAT) activity. The observed changes in HDAC activity and CBP levels also correlate with increased histone acetylation (H3-K9 and H4-K8) in the central and medial nucleus of amygdala, resulting in a relaxed chromatin structure. As a result, the transcriptional machinery can more easily access the DNA, leading to increased gene expression. Increased amygdaloid expression of certain genes, such as neuropeptide Y or brain-derived neurotrophic factor, may mediate the anxiolytic effects of acute ethanol exposure (Pandey et al. 2008a, b). Cellular tolerance at the level of HDAC-induced chromatin remodeling in the amygdala may be operative in rapid tolerance to the anxiolytic effects of ethanol (Sakharkar et al. 2012).NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; Ac = acetylation site.
Mentions: Correction of deficits in CBP function increasingly has become an important target in the treatment of neurological disorders, including Rubinstein-Taybi syndrome (RSTS), Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (Klevytska et al. 2010; Rouaux et al. 2004; Selvi et al. 2010). Mutations in the CBP gene are prevalent in RSTS (Alarcon et al. 2004; Bartsch et al. 2005; Roelfsema et al. 2005). For example, exon deletions in the genes that encode p300 and CBP have been detected in children with RSTS (Tsai et al. 2011). The changes in CBP function described in these neurological disorders are similar to neuroadaptations observed in alcoholism; therefore, CBP–HAT may be an important factor in the development of alcoholism (see figures 4 and 5).

Bottom Line: Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence.The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction.Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois.

ABSTRACT
Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism.

No MeSH data available.


Related in: MedlinePlus