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      Emerging Role of One-Carbon Metabolism and DNA Methylation Enrichment on δ-Containing GABA A Receptor Expression in the Cerebellum of Subjects with Alcohol Use Disorders (AUD)

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          Abstract

          Background

          Cerebellum is an area of the brain particularly sensitive to the effects of acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α 6/δ-containing GABA A receptors located on glutamatergic granule cells. Here, we studied whether chronic alcohol consumption induces changes in GABA A receptor subunit expression and whether these changes are associated with alterations in epigenetic mechanisms via DNA methylation.

          Methods

          We used a cohort of postmortem cerebellum from control and chronic alcoholics, here defined as alcohol use disorders subjects (n=25/group). S-adenosyl-methionine/ S-adenosyl-homocysteine were measured by high-performance liquid chromatography. mRNA levels of various genes were assessed by reverse transcriptase-quantitative polymerase chain reaction. Promoter methylation enrichment was assessed using methylated DNA immunoprecipitation and hydroxy-methylated DNA immunoprecipitation assays.

          Results

          mRNAs encoding key enzymes of 1-carbon metabolism that determine the S-adenosyl-methionine/ S-adenosyl-homocysteine ratio were increased, indicating higher “methylation index” in alcohol use disorder subjects. We found that increased methylation of the promoter of the δ subunit GABA A receptor was associated with reduced mRNA and protein levels in the cerebellum of alcohol use disorder subjects. No changes were observed in α 1- or α 6-containing GABA A receptor subunits. The expression of DNA-methyltransferases (1, 3A, and 3B) was unaltered, whereas the mRNA level of TET1, which participates in the DNA demethylation pathway, was decreased. Hence, increased methylation of the δ subunit GABA A receptor promoter may result from alcohol-induced reduction of DNA demethylation.

          Conclusion

          Together, these results support the hypothesis that aberrant DNA methylation pathways may be involved in cerebellar pathophysiology of alcoholism. Furthermore, this work provides novel evidence for a central role of DNA methylation mechanisms in the alcohol-induced neuroadaptive changes of human cerebellar GABA A receptor function.

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          Most cited references 53

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          Eukaryotic cytosine methyltransferases.

          Large-genome eukaryotes use heritable cytosine methylation to silence promoters, especially those associated with transposons and imprinted genes. Cytosine methylation does not reinforce or replace ancestral gene regulation pathways but instead endows methylated genomes with the ability to repress specific promoters in a manner that is buffered against changes in the internal and external environment. Recent studies have shown that the targeting of de novo methylation depends on multiple inputs; these include the interaction of repeated sequences, local states of histone lysine methylation, small RNAs and components of the RNAi pathway, and divergent and catalytically inert cytosine methyltransferase homologues that have acquired regulatory roles. There are multiple families of DNA (cytosine-5) methyltransferases in eukaryotes, and each family appears to be controlled by different regulatory inputs. Sequence-specific DNA-binding proteins, which regulate most aspects of gene expression, do not appear to be involved in the establishment or maintenance of genomic methylation patterns.
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            Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.

            Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Control of mental activities by internal models in the cerebellum.

               Masao ITO (2008)
              The intricate neuronal circuitry of the cerebellum is thought to encode internal models that reproduce the dynamic properties of body parts. These models are essential for controlling the movement of these body parts: they allow the brain to precisely control the movement without the need for sensory feedback. It is thought that the cerebellum might also encode internal models that reproduce the essential properties of mental representations in the cerebral cortex. This hypothesis suggests a possible mechanism by which intuition and implicit thought might function and explains some of the symptoms that are exhibited by psychiatric patients. This article examines the conceptual bases and experimental evidence for this hypothesis.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                December 2017
                19 August 2017
                19 August 2017
                : 20
                : 12
                : 1013-1026
                Affiliations
                Center of Alcohol Research in Epigenetics, Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, Illinois (Drs Gatta, Auta, Gavin, Bhaumik, Grayson, Pandey, Guidotti); Jesse Brown VA Medical Center, Chicago, Illinois (Drs Gavin and Pandey)
                Author notes
                Correspondence: Alessandro Guidotti, MD, Center for Alcohol Research in Epigenetics, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612 ( aguidotti@ 123456psych.uic.edu ).
                Article
                pyx075
                10.1093/ijnp/pyx075
                5716183
                29020412
                © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Page count
                Pages: 14
                Product
                Funding
                Funded by: University of Sydney 10.13039/501100001774
                Award ID: NIH-NIAAA R28AA012725
                Funded by: National Institute on Alcohol Abuse and Alcoholism 10.13039/100000027
                Award ID: P50AA022538
                Categories
                Regular Research Articles

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