The androgen receptor facilitates inhibition of human dopamine transporter (DAT1) reporter gene expression by HESR1 and HESR2 via the variable number of tandem repeats

摘要

A functional genetic polymorphism in the 3'-untranslated region (UTR) within exon 15 of the human . DAT gene (. DAT1) has been described. This 3'-UTR contains a variable number of tandem repeats (VNTR) 40. bp in length; many association studies of psychiatric or developmental disorders with this VNTR have been conducted. We previously demonstrated that HESR1 (the Hairy/enhancer of split related transcriptional factor 1 with YRPW motif) and HESR2 reduced . DAT reporter gene expression via this 3'-UTR. VNTR allele-dependent altered reporter gene expression was also observed. In the present study, we wanted to clarify the molecular characterization of HESR1 and HESR2, focusing on its . cis-element and co-factor. Deletion of the VNTR domain increased reporter gene expression both with and without transfection of HESRs, suggesting that the VNTR inhibits . DAT expression, and is responsive to HESRs. In the presence of transfected androgen receptor (AR), activity of the luciferase reporter with the nine-repeat allele (9r) decreased, while that with the ten-repeat allele (10r), the most frequent in the population, increased significantly. Furthermore, co-expression of HESR1 or HESR2 with AR increased the inhibitory effect of the HESRs. Our data indicate that a functional modification occurs when the HESRs are coupled with AR. This HESR-AR interaction could be the molecular basis of sexual dimorphisms in DAT expression, or other dopamine-related behavioral traits.