Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Rita Cervera-Juanes, Larry J. Wilhelm, Byung Park, Kathleen (Kathy) Grant, Betsy Ferguson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens core (NAcc) of male rhesus macaques categorized as low or binge drinkers, compared to alcohol-naïve and heavy drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n = 24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to . PDE10A and . PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the . CCBE1 and . FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to . FZD5 and . PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.

Original languageEnglish (US)
JournalAlcohol
DOIs
StateAccepted/In press - Sep 19 2016

Fingerprint

Methylation
Nucleus Accumbens
DNA Methylation
Alcohol Drinking
Genes
alcohol
Alcohols
Genome
Gene expression
escalation
Gene Expression
Drinking
self-administration
regional analysis
Binge Drinking
Drinking Behavior
Wnt Signaling Pathway
Gene encoding
Self Administration
Cell Adhesion Molecules

Keywords

  • Alcohol
  • Differentially methylated regions
  • DNA methylation
  • Exon-usage
  • Gene expression
  • Nonhuman primates

ASJC Scopus subject areas

  • Health(social science)
  • Medicine(all)
  • Biochemistry
  • Toxicology
  • Neurology
  • Behavioral Neuroscience

Cite this

@article{7776439ef0bd483ca0a5e24472bf6daa,
title = "Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking",
abstract = "Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens core (NAcc) of male rhesus macaques categorized as low or binge drinkers, compared to alcohol-na{\"i}ve and heavy drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol na{\"i}ve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n = 24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to . PDE10A and . PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the . CCBE1 and . FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to . FZD5 and . PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.",
keywords = "Alcohol, Differentially methylated regions, DNA methylation, Exon-usage, Gene expression, Nonhuman primates",
author = "Rita Cervera-Juanes and Wilhelm, {Larry J.} and Byung Park and Grant, {Kathleen (Kathy)} and Betsy Ferguson",
year = "2016",
month = "9",
day = "19",
doi = "10.1016/j.alcohol.2016.11.003",
language = "English (US)",
journal = "Alcohol",
issn = "0741-8329",
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T1 - Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

AU - Cervera-Juanes, Rita

AU - Wilhelm, Larry J.

AU - Park, Byung

AU - Grant, Kathleen (Kathy)

AU - Ferguson, Betsy

PY - 2016/9/19

Y1 - 2016/9/19

N2 - Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens core (NAcc) of male rhesus macaques categorized as low or binge drinkers, compared to alcohol-naïve and heavy drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n = 24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to . PDE10A and . PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the . CCBE1 and . FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to . FZD5 and . PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.

AB - Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens core (NAcc) of male rhesus macaques categorized as low or binge drinkers, compared to alcohol-naïve and heavy drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n = 24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to . PDE10A and . PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the . CCBE1 and . FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to . FZD5 and . PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.

KW - Alcohol

KW - Differentially methylated regions

KW - DNA methylation

KW - Exon-usage

KW - Gene expression

KW - Nonhuman primates

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