SE-driven metabolic reprogramming in ADPKD (RNA-Seq)
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ABSTRACT:
PROVIDER: PRJNA592997 | ENA |
REPOSITORIES: ENA
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Project description:SE-driven metabolic reprogramming in ADPKD
| PRJNA592996 | ENA
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 (ChIP-Seq)
| PRJNA592998 | ENA
Project description:SE-driven metabolic reprogramming in ADPKD (kidney RNA-seq)
| PRJNA611748 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-05-16 | GSE141281 | GEO
Project description:Intrauterine hyperglycemia has been linked to an elevated risk of diabetes in next and further generations. Existing reports about transmission effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, the impact of intrauterine hyperglycemia per se has not been separately assessed. To investigate effect of intrauterine hyperglycemia exposure per se on further generations, we selected non-phenotypic F1-GDM and F2-GDM male mice to examin metabolic changes in next generation and performed a methylome on day 13.5 primordial germ cells (PGCs) of F1-GDM male fetus to explore its underlying mechanism. We found that intrauterine hyperglycemia exposure per se resulted in obesity, insulin resistance and/or glucose intolerance in F2 male mice, and no changes in F3 male mice. Methylome of day 13.5 PGCs of F1-GDM male fetus revealed differently methylation genes enriched in obesity and diabetic pathogenesis. Methylation validation of targeted gene Fyn showed consistent hypo-methylation status in F1 PGCs, F1 fetal testis, sperm of F1/N-GDM mice, and somatic cells of F2-GDM male mice. While fetal testis of F2-GDM mice showed no alteration in Fyn methylation. Our data indicates that intrauterine hyperglycemia exposure per se contributes to metabolic changes in F2 but not F3 generation, by altering methylation erasure in PGCs of F1 generation.
2017-12-20 | GSE108319 | GEO
Project description:Intrauterine hyperglycemia exposure per se altered metabolic functions in F2 offspring via reprogramming F1 PGCs
| PRJNA423101 | ENA
Project description:High fructose diet has been proposed as a major contributor to metabolic syndrome, which is usually accompanied with proteinuria due to glomerular podocyte injury. However, the underlying pathological mechanisms of fructose-induced podocyte injury remain elusive. In this study, we have used an iTRAQ based quantitative proteomic strategy to comprehensively characterize the dynamic proteome changes in glomeruli of high fructose-fed rats, and revealed global fructose-induced glomerular metabolic reprogramming at four different stages during the progression of high fructose modeling.
2022-05-19 | PXD017849 | Pride