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Intragenic Transcriptional cis-Antagonism Across SLC6A3

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Abstract

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.

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Funding

This work is supported by NIH grants DA021409 and DA031573 to ZL; YZ, JZ, XC, and NX were supported by Chinese Government Visiting Scholarships.

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Author notes

  1. Ying Zhao, Jinlong Yu, and Juan Zhao contributed equally to this work.

Authors and Affiliations

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

    Ying Zhao, Jinlong Yu, Juan Zhao, Xiaowu Chen, Nian Xiong & Zhicheng Lin

  2. School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China

    Ying Zhao

  3. College of Life Science, Beijing Institute of Technology, Beijing, 100081, China

    Juan Zhao & Hong Qing

  4. Department of Neurology, Shenzhen University General Hospital, Shenzhen, Guangzhou, 518060, China

    Xiaowu Chen

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

    Nian Xiong & Tao Wang

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  1. Ying Zhao
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  2. Jinlong Yu
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  3. Juan Zhao
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  4. Xiaowu Chen
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  8. Zhicheng Lin
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Contributions

ZL, TW, and HQ designed study; YZ, JY, JZ, XC, NX, and ZL participated in experiments and data analysis; and ZL wrote the manuscript.

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Correspondence to Zhicheng Lin.

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Zhao, Y., Yu, J., Zhao, J. et al. Intragenic Transcriptional cis-Antagonism Across SLC6A3. Mol Neurobiol 56, 4051–4060 (2019). https://doi.org/10.1007/s12035-018-1357-5

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