Is DNA methylation in the brain a mechanism of alcohol use disorder?

Jarczak, Justyna; Miszczak, Michalina; Radwańska, Kasia

doi:10.3389/fnbeh.2023.957203

Cited by 5 publications

(3 citation statements)

References 116 publications

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“…Similar over-represented gene ontology categories were also found to be differentially regulated following binge ethanol in the PFC of adolescent DBA/2J mice in prior studies ( Wolstenholme et al, 2017 ; Brocato and Wolstenholme, 2023 ). Epigenetic regulation through histone demethylase activity is particularly intriguing as a growing number of studies show ethanol alters methylation marks ( Bohnsack and Pandey, 2021 ; Brocato and Wolstenholme, 2021 ; Siomek-Gorecka et al, 2021 ; Jarczak et al, 2023 ) and inhibits the production of methyl substrates ( Watson et al, 2011 ; Brocato and Wolstenholme, 2021 ; Jarczak et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice

Lodha,

Brocato,

Nash

et al. 2023

Front. Neurosci.

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IntroductionAdolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome.MethodsAdolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis.ResultsAs adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex.DiscussionThe behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens.

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Section: Discussionmentioning

confidence: 99%

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice

Lodha,

Brocato,

Nash

et al. 2023

Front. Neurosci.

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“…DNA methylation (DNAm) is an epigenetic mark that contributes to modulation of gene expression by modifying the accessibility of transcription factors to chromatin. Alterations in DNAm are reported in heavy drinking humans, monkeys and rodents 3 – 5 , 35 , 36 , and a recent study demonstrated that knockdown of DNA methyltransferases reduced Kcnn3 expression and increased intrinsic excitability of cultured cortical neurons 37 . Thus, we measured DNAm levels at a differentially methylated region in exon 1 (MR-ex1) that coincides with a cross-species regulatory region within the KCNN3 promoter.…”

Section: Introductionmentioning

confidence: 99%

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.

Juanes,

Mulholland,

Padula

et al. 2023

Preprint

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The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca2+-activated K+ (KCa2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol dependent mice. Here, this cross-species analysis focused on KCNN3 DNA methylation, gene expression, and single nucleotide polymorphisms including alternative promoters in KCNN3 that could influence surface trafficking and function of KCa2 channels. Bisulfite sequencing analysis of the nucleus accumbens tissue from alcohol-drinking monkeys and alcohol dependent mice revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in the accumbens paralleled an increase in expression of alternative transcripts that encode apamin-insensitive and dominant-negative KCa2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, KCa2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.

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“…DNA methylation (DNAm) is an epigenetic mark that contributes to the modulation of gene expression by modifying the accessibility of transcription factors to chromatin. Alterations in DNAm are reported in heavy-drinking humans, monkeys and rodents [ 3 – 5 , 35 , 36 ], and a recent study demonstrated that knockdown of DNA methyltransferases reduced Kcnn3 expression and increased intrinsic excitability of cultured cortical neurons [ 37 ]. Thus, we measured DNAm levels at a differentially methylated region (DMR) in exon 1 (MR-ex1) that coincides with a cross-species regulatory region within the KCNN3 promoter.…”

Section: Introductionmentioning

confidence: 99%

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking

Mulholland,

Padula,

Wilhelm

et al. 2023

Transl Psychiatry

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The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca2+-activated K+ (KCa2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol-dependent mice. Here, this cross-species analysis focused on KCNN3 DNA methylation, gene expression, and single nucleotide polymorphisms, including alternative promoters in KCNN3, that could influence surface trafficking and function of KCa2 channels. Bisulfite sequencing analysis of the nucleus accumbens tissue from alcohol-drinking monkeys and alcohol-dependent mice revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in the accumbens paralleled an increase in the expression of alternative transcripts that encode apamin-insensitive and dominant-negative KCa2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, KCa2.3 channel expression in the accumbens was significantly reduced in very heavy-drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 represent a complex mechanism that utilizes alternative promoters to potentially impact the firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.

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Is DNA methylation in the brain a mechanism of alcohol use disorder?

Cited by 5 publications

References 116 publications

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking

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