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Series GSE141279 Query DataSets for GSE141279
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
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.
 
Overall design ChIPmentation sequencing with H3K27ac antibody in pkd1 and null cell lines.
 
Contributor(s) Mi Z, Chen Y
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Dec 02, 2019
Last update date May 17, 2020
Contact name Zeyun Mi
E-mail(s) mizeyun@tmu.edu.cn
Phone 15900207057
Organization name Tianjin Medical University
Street address Qi Xiang Tai Road
City Tianjin
ZIP/Postal code 300070
Country China
 
Platforms (1)
GPL23479 BGISEQ-500 (Mus musculus)
Samples (4)
GSM4200336 pkd1_input
GSM4200337 null_input
GSM4200338 pkd1_H3K27ac
This SubSeries is part of SuperSeries:
GSE141281 SE-driven metabolic reprogramming in ADPKD
Relations
BioProject PRJNA592998
SRA SRP234427

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE141279_null_ChIP.wiggle.tar.gz 23.0 Mb (ftp)(http) TAR
GSE141279_pkd1_ChIP.wiggle.tar.gz 24.1 Mb (ftp)(http) TAR
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Raw data are available in SRA
Processed data are available on Series record

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