A G-quadruplex nanoswitch in the SGK1 promoter regulates isoform expression by K+/Na+ balance and resveratrol binding

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 2; p. 129778
• Main Authors: Chen, Mengjie, Chen, Qi, Li, Yirui, Yang, Zhenjun, Taylor, Ethan W., Zhao, Lijun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2021
• Subjects: Animals; Antihypertensive Agents - metabolism; Antihypertensive Agents - pharmacology; blood pressure; Dietary sodium guidelines; drug development; epithelium; G-Quadruplexes - drug effects; Gene expression; genes; HEK293 Cells; Humans; hypertension; Immediate-Early Proteins - genetics; Models, Molecular; potassium; Potassium - metabolism; Potassium - pharmacology; Promoter Regions, Genetic - drug effects; Protein-Serine-Threonine Kinases - genetics; resveratrol; Resveratrol - metabolism; Resveratrol - pharmacology; Salt-sensitive hypertension; sodium; Sodium - metabolism; Sodium - pharmacology; sodium channels; Transcriptional Activation - drug effects; vegetarian diet; Western blotting; Dietary sodium guidelines; Salt-sensitive hypertension; Gene expression; G4
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129778

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. 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. 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. Stabilizing the G4 by potassium or resveratrol induces alternative promoter usage and/or pre-mRNA splicing in the transcription of SGK1. 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. [Display omitted] •A G-quadruplex in the SGK1 promoter is a molecular switch for isoform expression.•The G-quadruplex is stabilized by K+ or Resveratrol, but destabilized by Na+.•Potassium supplementation inhibits the transcription of SGK1 isoforms.