title: Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers.
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).
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bannon
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Candace L
authors.initials: CL
authors.lastname: Savonen
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dachet
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Halter
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Schmidt
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.|Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Lipovich
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA.|Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kapatos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008636:Mesencephalon / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D014158:Transcription, Genetic; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D062085:RNA, Long Noncoding; C414202:TRAF3IP2 protein, human; C413404:TRAF3IP2-AS1 antisense RNA, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D012313:RNA; D003042:Cocaine; D004298:Dopamine
keywords: cocaine; dopamine; drug abuse; gene expression; long noncoding RNA; postmortem