AZI23′UTR is a new SLC6A3 downregulator associated with an epistatic protection against substance use disorders

摘要

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 cloned a new transcription active unit, ^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 down regulate promoter activity though a variant-dependent mechanism in vitro Both reduced RNA density ratio of ^AZI23′UTR/AZI2 and increased DAT mRNA levels were found in ethanol-naïve 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.