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A G-quadruplex nanoswitch in the SGK1 promoter regulates isoform expression by K+/Na+ balance and resveratrol binding
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-11-02 , DOI: 10.1016/j.bbagen.2020.129778
Mengjie Chen , Qi Chen , Yirui Li , Zhenjun Yang , Ethan W. Taylor , Lijun Zhao

Background

High sodium intake can up-regulate the level of renal serum- and glucocorticoid-inducible kinase-1 (SGK1), which plays a pivotal role in controlling blood pressure via activation of the epithelial sodium channel (ENaC), which can lead to salt-sensitive hypertension. Increased potassium intake, or a vegetarian diet, counteracts salt-sensitive hypertension, but the underlying mechanisms are not fully understood.

Methods

Bioinformatics and molecular modeling were used to identify G-quadruplex (G4) and their conformations in the SGK1 promoter. CD spectra and UV melting dynamics were measured to study the stability of G4 as influenced by potassium/sodium balance and resveratrol. RT-PCR and Western blot were employed to study the effects of potassium and resveratrol on the SGK1 isoform expression.

Results

The SGK1 gene encodes a G4 structure in the proximal upstream of promoter-2; the G4 structure is stabilized by potassium or resveratrol, but destabilized by sodium. Super-physiological levels of sodium stimulate the transcription of all SGK1 isoforms, whereas resveratrol or potassium supplementation inhibits the transcription of iso-2 and iso-3, but not iso-1.

Conclusions

Stabilizing the G4 by potassium or resveratrol induces alternative promoter usage and/or pre-mRNA splicing in the transcription of SGK1.

General significance

Potassium/sodium ion balance or resveratrol binding can act to regulate G4 molecular switches for controlling SGK1 gene expression, thereby presenting a new avenue for drug development.



中文翻译:

SGK1启动子中的G四联体纳米开关通过K + / Na +平衡和白藜芦醇结合调节同工型表达

背景

高钠摄入量可以上调肾脏血清和糖皮质激素诱导的激酶1(SGK1)的水平,它通过激活上皮钠通道(ENaC)在控制血压中起关键作用,这可以导致盐分升高。敏感性高血压。增加钾的摄入量或素食可以抵消对盐敏感的高血压,但其潜在机制尚不完全清楚。

方法

使用生物信息学和分子建模来鉴定G-四链体(G4)及其在SGK1启动子中的构象。测量了CD光谱和UV熔融动力学,以研究G4的稳定性,该稳定性受钾/钠平衡和白藜芦醇的影响。采用RT-PCR和Western blot研究钾和白藜芦醇对SGK1同工型表达的影响。

结果

SGK1基因在启动子2的近端上游编码G4结构。G4结构由钾或白藜芦醇稳定,但由钠不稳定。钠的超生理水平会刺激所有SGK1亚型的转录,而白藜芦醇或钾的添加会抑制iso-2和iso-3的转录,但不会抑制iso-1的转录。

结论

通过钾或白藜芦醇稳定G4可以诱导SGK1转录中替代启动子的使用和/或pre-mRNA剪接。

一般意义

钾/钠离子平衡或白藜芦醇结合可起调节G4分子开关的作用,从而控制SGK1基因表达,从而为药物开发提供了新途径。

更新日期:2020-11-06
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