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Series GSE141740 Query DataSets for GSE141740
Status Public on Jan 26, 2021
Title Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [RNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Oxidative stress is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed redox homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of Nrf2 antioxidant pathway as a driver mechanism for oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemistry analyses, we find that Nrf2 antioxidant pathway is suppressed due to increased degradation of Nrf2 protein in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the ROS levels inversely correlates with Nrf2 abundance and positively correlates with disease severity. Genetic deletion of Nrf2 further increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of Nrf2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, pharmacological induction of Nrf2 remodels enhancer landscapes and activates Nrf2-bound enhancer-associated genes in ADPKD cells. The activation domain of Nrf2 forms phase-separated condensates with Mediator subunit MED16 in vitro, and Nrf2 is required for optimal Mediator recruitment to target genomic loci in vivo. Taken together, these findings indicate that Nrf2 remodels enhancer landscapes and activates its target genes through a phase-separation mechanism, and that activation of Nrf2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.
Overall design We performed gene expression analysis on mRNA from normal and Nrf2 knockout WT 9-12 cells treated with vehicle or SFN.
Contributor(s) Chen Y, Liu Z
Citation(s) 32727915
Submission date Dec 10, 2019
Last update date Jan 29, 2021
Contact name Zhiheng Liu
Organization name Tianjin Medical University
Department Tianjin Research Center for Basic Medical Science
Lab Gene Expression Laboratory
Street address No.22 Qixiangtai Road
City Tianjin
State/province Tianjin
ZIP/Postal code 300070
Country China
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (8)
GSM4212645 DMSO_rep1
GSM4212646 DMSO_rep2
GSM4212647 SFN_rep1
This SubSeries is part of SuperSeries:
GSE141741 Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
BioProject PRJNA594607
SRA SRP235550

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Supplementary file Size Download File type/resource
GSE141740_RAW.tar 1.2 Mb (http)(custom) TAR (of TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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