Laboratory of Psychiatric Neurogenomics, Basic Neuroscience Division, McLean Hospital, Belmont, MA, 02478, USA.
School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China.
Mol Neurobiol. 2019 Jun;56(6):4051-4060. doi: 10.1007/s12035-018-1357-5. Epub 2018 Sep 27.
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.
启动子可受多种顺式作用元件调控,因此阐明这些元件的调控模式有助于理解基因活性的发育、环境和遗传机制。在这里,我们报告人类多巴胺转运体基因 SLC6A3 带有一个 5'远端 5kb 超增强子(5KSE),可使启动子的活性增加 5 倍。有趣的是,5KSE 能够防止 3'下游可变数串联重复序列(3'VNTRs)沉默启动子。这个新的增强子由一个 5'VNTR 和三个在灵长类动物中保守的重复亚元件组成。5KSE 的两个亚元件 E-9.7 和 E-8.7 可上调启动子,但只有后者在存在 3'VNTRs 的情况下仍能继续这样做。最后,E-8.7 被包括 SRP54 和 Nfe2l1 在内的新型多巴胺能转录因子激活。综上所述,这些结果揭示了 SLC6A3 中存在一种多模式调控机制。