Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence

Abstract

Background: Long noncoding RNA (lncRNA) have been implicated in the etiology of alcohol use. Since lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step toward understanding lncRNA functions in alcohol use and addiction. Thus, we sought to profile lncRNA expression in the nucleus accumbens (NAc) in a large postmortem alcohol brain sample. Methods: LncRNA and protein-coding gene (PCG) expressions in the NAc from 41 subjects with alcohol dependence (AD) and 41 controls were assessed via a regression model. Weighted gene coexpression network analysis was used to identify lncRNA and PCG networks (i.e., modules) significantly correlated with AD. Within the significant modules, key network genes (i.e., hubs) were also identified. The lncRNA and PCG hubs were correlated via Pearson correlations to elucidate the potential biological functions of lncRNA. The lncRNA and PCG hubs were further integrated with GWAS data to identify expression quantitative trait loci (eQTL). Results: At Bonferroni adj. p-value ≤ 0.05, we identified 19 lncRNA and 5 PCG significant modules, which were enriched for neuronal and immune-related processes. In these modules, we further identified 86 and 315 PCG and lncRNA hubs, respectively. At false discovery rate (FDR) of 10%, the correlation analyses between the lncRNA and PCG hubs revealed 3,125 positive and 1,860 negative correlations. Integration of hubs with genotype data identified 243 eQTLs affecting the expression of 39 and 204 PCG and lncRNA hubs, respectively. Conclusions: Our study identified lncRNA and gene networks significantly associated with AD in the NAc, coordinated lncRNA and mRNA coexpression changes, highlighting potentially regulatory functions for the lncRNA, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

“…2a and Supplementary Data 2). Within these sexually dimorphic proteins, we identified proteins previously implicated in reward-and drug-associated responses, such as GRM2 22 , VPS51 23 , SATT 24 , VGLU3 25 , IPO4 26 , VAMP1 27 , and CYFP2 28 (Fig. 2b).…”

Exploration of alcohol use disorder-associated brain miRNA–mRNA regulatory networks

“…The lmfit function in the limma package [ 35 ] was then used to fit a linear regression model using the weighted least square for each gene, and comparisons between case and control groups in log 2 fold-changes (log 2 FC) were obtained as contrasts of the fitted linear model, with a number of confounding factors being considered as covariates. We did principal component analysis (PCA) to extract the first three PCs for both technical (batch, RIN, and PMI) and biological (sex, age, brain weight, brain pH, left-right brain, smoking, and liver disease) confounding variables, and the obtained PC1, PC2, and PC3 were used as covariates in the model matrix design for differential expression analysis, as described in a recent article [ 36 ]. For microarray expression data from Set 2 brain tissue samples, the differential expression analysis was performed in the same way using the lmfit function in the limma package [ 35 ].…”

RNA m6A Modification Changes in Postmortem Nucleus Accumbens of Subjects with Alcohol Use Disorder: A Pilot Study

“…In our recent study with the use of RNA sequencing (RNA-seq) to profile mRNA and microRNA (miRNA) transcriptomic changes in postmortem NAc of AUD subjects, we unraveled AUD-associated mRNA-miRNA pairs and their potentially influenced pathways (such as the CREB signaling in neurons) [ 26 ]. Recently, Drake et al assessed the role of long-noncoding RNA (lncRNAs) in postmortem NAc of AUD subjects [ 27 ]. To understand the epigenetic mechanisms behind alcohol-induced neuroadaptative changes in the NAc, Cervera-Juanes et al used rhesus macaques as models to identify NAc DNA methylation signals that distinguished alcohol-naive (AN), low/binge (L/BD), and heavy/very heavy (H/VHD) drinking primates [ 28 ].…”