A promoter can be regulated by various cis-acting elements so that delineation of the regulatory modes among them may help understand developmental, environmental and genetic mechanisms in gene activity. Here we report that the human dopamine transporter gene SLC6A3 carries a 5' distal 5-kb super enhancer (5KSE) which upregulated the promoter by 5-fold. Interestingly, 5KSE is able to prevent 3' downstream variable number tandem repeats (3'VNTRs) from silencing the promoter. This new enhancer consists of a 5'VNTR and three repetitive sub-elements that are conserved in primates. Two of 5KSE's sub-elements, E-9.7 and E-8.7, upregulate the promoter, but only the later could continue doing so in the presence of 3'VNTRs. Finally, E-8.7 is activated by novel dopaminergic transcription factors including SRP54 and Nfe2l1. Together, these results reveal a multimodal regulatory mechanism in SLC6A3.

College of Life Science Beijing Institute of Technology Beijing 100081 China

Department of Neurology Shenzhen University General Hospital Shenzhen Guangzhou 518060 China

Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Laboratory of Psychiatric Neurogenomics Basic Neuroscience Division McLean Hospital Belmont MA 02478 USA

School of Pharmacy Xinxiang Medical University Xinxiang 453003 China

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The dopamine transporter gene SLC6A3: multidisease risks

Identification of HIVEP2 as a dopaminergic transcription factor related to substance use disorders in rats and humans