Abstract
Maintenance of the drug‐addicted state is thought to involve changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine (DA) neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but next to nothing is known about their role in drug abuse. The proportion of lncRNAs that are primate‐specific provides a strong rationale for their study in human drug abusers. In this study, we determined a profile of dysregulated putative lncRNAs through the analysis of postmortem human midbrain specimens from chronic cocaine abusers and well‐matched control subjects (n = 11 in each group) using a custom lncRNA microarray. A dataset comprising 32 well‐annotated lncRNAs with independent evidence of brain expression and robust differential expression in cocaine abusers is presented. For a subset of these lncRNAs, differential expression was validated by quantitative real‐time PCR and cellular localization determined by in situ hybridization histochemistry. Examples of lncRNAs exhibiting DA cell‐specific expression, different subcellular distributions, and covariance of expression with known cocaine‐regulated protein‐coding genes were identified. These findings implicate lncRNAs in the cellular responses of human DA neurons to chronic cocaine abuse. Long noncoding RNAs (lncRNAs) regulate the expression of protein‐coding genes, but little is known about their potential role in drug abuse. In this study, we identified lncRNAs differentially expressed in human cocaine abusers' midbrains. One up‐regulated antisense lncRNA, tumor necrosis factor receptor‐associated factor 3‐interacting protein 2‐antisense 1 (TRAF3IP2‐AS1), was found predominantly in the nucleus of human dopamine (DA) neurons, whereas the related TRAF3IP2 protein‐coding transcript was distributed throughout these cells. The abundances of these transcripts were significantly correlated (left) suggesting that TRAF3IP2‐AS1 may regulate TRAF3IP2 gene expression, perhaps through local chromatin changes at this locus (right).
Highlights
For the purposes of this study, a putative long noncoding RNA (lncRNA) transcript was initially classified as differentially expressed in cocaine abusers versus control subjects only if the signal intensity of all seven non-identical microarray probes sequences was significantly different, as determined by ANOVA with an false discovery rate of 5%
To restrict subsequent analysis to the most robustly changed and wellannotated of these transcripts, the dataset was further pared down using both a magnitude of difference threshold (≥ 1.3 average fold difference) and the requirement of independent evidence of expression in brain. Application of this stringent set of criteria yielded a final list of 32 well-annotated lncRNAs exhibiting robust differential expression (14 were up-regulated and 18 were downregulated) in the midbrains of human cocaine abusers (Table 2)
The major goal of this study was to identify lncRNAs that are significantly dysregulated in the ventral midbrain of human cocaine abusers
Summary
As approximately one-third of the thousands of human lncRNAs identified appear to be unique to the primate lineage (Derrien et al 2012), there is a compelling rationale for studying lncRNAs in the drug-addicted human brain as well as simpler model systems. To address this significant gap in knowledge, this study investigated lncRNA expression in the postmortem midbrain of human cocaine abusers and well-matched control subjects. LncRNAs exhibiting DA cellspecific expression, different subcellular distributions, and covariance of expression with known cocaine-regulated protein-coding genes were identified.
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