SE-driven metabolic reprogramming in ADPKD
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA592996 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10574258.fastq.gz | Fastqsanger.gz | |||
| SRR10574259.fastq.gz | Fastqsanger.gz | |||
| SRR10574260.fastq.gz | Fastqsanger.gz | |||
| SRR10574261.fastq.gz | Fastqsanger.gz | |||
| SRR10574262.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-05-16 | GSE141279 | GEO
Project description: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.
2020-05-16 | GSE141280 | GEO
Project description: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.
2020-05-16 | GSE146714 | GEO
Project description:SE-driven metabolic reprogramming in ADPKD (RNA-Seq)
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2020-05-16 | GSE141281 | GEO
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2017-12-20 | GSE108319 | GEO
Project description:Intrauterine hyperglycemia exposure per se altered metabolic functions in F2 offspring via reprogramming F1 PGCs
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