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| 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
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| 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.
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| Overall design |
We performed gene expression analysis on mRNA from normal and Nrf2 knockout WT 9-12 cells treated with vehicle or SFN.
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| Contributor(s) |
Chen Y, Liu Z |
| Citation(s) |
32727915 |
| Submission date |
Dec 10, 2019 |
| Last update date |
Jan 29, 2021 |
| Contact name |
Zhiheng Liu |
| E-mail(s) |
liuzhiheng@tmu.edu.cn
|
| Organization name |
Tianjin Medical University
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| Department |
Tianjin Research Center for Basic Medical Science
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| Lab |
Gene Expression Laboratory
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| Street address |
No.22 Qixiangtai Road
|
| City |
Tianjin |
| State/province |
Tianjin |
| ZIP/Postal code |
300070 |
| Country |
China |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE141741 |
Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease |
|
| Relations |
| BioProject |
PRJNA594607 |
| SRA |
SRP235550 |
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