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Status |
Public on May 16, 2020 |
Title |
SE-driven metabolic reprogramming in ADPKD (ChIP-Seq) |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
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Overall design |
ChIPmentation sequencing with H3K27ac antibody in pkd1 and null cell lines.
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Contributor(s) |
Mi Z, Chen Y |
Citation missing |
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Submission date |
Dec 02, 2019 |
Last update date |
May 17, 2020 |
Contact name |
Zeyun Mi |
E-mail(s) |
mizeyun@tmu.edu.cn
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Phone |
15900207057
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Organization name |
Tianjin Medical University
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Street address |
Qi Xiang Tai Road
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City |
Tianjin |
ZIP/Postal code |
300070 |
Country |
China |
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Platforms (1) |
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Samples (4)
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This SubSeries is part of SuperSeries: |
GSE141281 |
SE-driven metabolic reprogramming in ADPKD |
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Relations |
BioProject |
PRJNA592998 |
SRA |
SRP234427 |