AZI23’UTR Is a New SLC6A3 Downregulator Associated with an Epistatic Protection Against Substance Use Disorders

Kefu Liu, Jinlong Yu, Juan Zhao, Yanhong Zhou, Nian Xiong, Jie Xu, Tao Wang, Richard L. Bell, Hong Qing, Zhicheng Lin

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Regulated activity of SLC6A3, which encodes the human dopamine transporter (DAT), contributes to diseases such as substance abuse disorders (SUDs); however, the exact transcription mechanism remains poorly understood. Here, we used a common genetic variant of the gene, intron 1 DNP1B sequence, as bait to screen and clone a new transcriptional activity, AZI23′UTR, for SLC6A3. AZI23′UTR is a 3′ untranslated region (3′UTR) of the human 5-Azacytidine Induced 2 gene (AZI2) but appeared to be transcribed independently of AZI2. Found to be present in both human cell nuclei and dopamine neurons, this RNA was shown to downregulate promoter activity through a variant-dependent mechanism in vitro. Both reduced RNA density ratio of AZI23′UTR/AZI2 and increased DAT mRNA levels were found in ethanol-naive alcohol-preferring rats. Secondary analysis of dbGaP GWAS datasets (Genome-Wide Association Studies based on the database of Genotypes and Phenotypes) revealed significant interactions between regions upstream of AZI23′UTR and SLC6A3 in SUDs. Jointly, our data suggest that AZI23′UTR confers variant-dependent transcriptional regulation of SLC6A3, a potential risk factor for SUDs.

Original languageEnglish (US)
Pages (from-to)5611-5622
Number of pages12
JournalMolecular Neurobiology
Volume55
Issue number7
DOIs
StatePublished - Jul 1 2018

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Keywords

  • Allele-dependent
  • Dopamine transporter
  • Kangaroo layout of genes
  • Ribonucleic repressor
  • Transcription factor
  • lncRNA

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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