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Integrative Low-input Transcriptomic and Cistromic Analyses Identify CREB Target Genes in Cystic Epithelial Cells [CUT&RUN, ChIP-Seq]

ABSTRACT: Transcription factors (TFs) play crucial roles in kidney development and disease by recognizing specific DNA sequences to control gene expression programs. The kidney’s cellular heterogeneity poses substantial challenges to identifying the genomic binding sites and direct target genes of TFs in vivo. We apply the CUT&RUN (cleavage under targets and release using nuclease) technique, together with transcriptomic analysis, to identify cAMP-response element-binding protein (CREB) target genes in cystic epithelial cells of autosomal dominant polycystic kidney disease (ADPKD). Our results reveal that CREB binds to and activates ribosomal biogenesis genes, and that inhibition of CREB retards cyst growth in ADPKD mouse models. Our findings demonstrate that CUT&RUN is a powerful method for genome-scale profiling and identifying direct targets of TFs from small numbers of specific kidney cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE165416 | GEO | 2022/01/01

REPOSITORIES: GEO

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Integrative Low-input Transcriptomic and Cistromic Analyses Identify CREB Target Genes in Cystic Epithelial Cells [RNA-Seq]

Project description:Transcription factors (TFs) play crucial roles in kidney development and disease by recognizing specific DNA sequences to control gene expression programs. The kidney’s cellular heterogeneity poses substantial challenges to identifying the genomic binding sites and direct target genes of TFs in vivo. We apply the CUT&RUN (cleavage under targets and release using nuclease) technique, together with transcriptomic analysis, to identify cAMP-response element-binding protein (CREB) target genes in cystic epithelial cells of autosomal dominant polycystic kidney disease (ADPKD). Our results reveal that CREB binds to and activates ribosomal biogenesis genes, and that inhibition of CREB retards cyst growth in ADPKD mouse models. Our findings demonstrate that CUT&RUN is a powerful method for genome-scale profiling and identifying direct targets of TFs from small numbers of specific kidney cells.

2022-01-01 | GSE165417 | GEO

Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

Project description:Mitochondrial dysfunction is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed mitochondrial homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of NRF2 antioxidant pathway as a driver mechanism for mitochondrial dysfunction and ADPKD progression. Using a quantitative proteomic approach, we find that NRF2 antioxidant pathway is suppressed in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the increased ROS levels inversely correlates with decreased NRF2 expression and positively correlates with disease severity. Genetic deletion of NRF2 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, NRF2 activates its antioxidant target genes mainly through remodeling enhancer landscapes. The activation domain of NRF2 forms phase-separated condensates with MED16, a Mediator complex subunit in vitro, and NRF2 is required for optimal Mediator recruitment to target genomic sites 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 mitochondrial homeostasis and combatting ADPKD.

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Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [RNA-seq]

Project description: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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Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-seq]

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Project description:We performed CUT&RUN sequencing to characterize HNF4A binding sites in human adult kidney and kidney organoid-derived proximal tubular cells.

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Dual inhibition of oxidative stress and CREB transcription activity by melanin-like nanoparticles slows cyst growth in autosomal dominant polycystic kidney disease

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Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD.

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Chromatin conformation and histone modification profiling across human kidney anatomic regions [CUT&RUN]

Project description:Here, we leveraged our recently described high-yield nuclei extraction method and performed Hi-C and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing of histone modifications (H3K4me3 and H3K27me3) in parallel on the kidney cortex, medulla and papilla samples dissected from the same donor. This site describes the CUT&RUN data.

2024-06-20 | GSE253630 | GEO

Proteomic Analysis of Urinary Extracellular Vesicles

Project description:Novel therapies in autosomal dominant polycystic kidney disease (ADPKD) signal the need for markers of disease progression or response to therapy. This study aimed to identify disease-associated proteins in urinary extracellular vesicles (uEVs), which include exosomes, in patients with ADPKD. We performed quantitative proteomics on uEVs using a labeled approach (healthy vs. ADPKD) and then using a label-free approach in different subjects (healthy vs. ADPKD vs. non-ADPKD chronic kidney disease [CKD]). In both experiments, thirty proteins were consistently more abundant (≥ 2-fold) in ADPKD-uEVs compared with healthy and CKD uEVs. Of these proteins, periplakin, envoplakin, villin-1, complement C3 and C9 were selected for confirmation, because (1) they were also significantly overrepresented in pathway analysis, and (2) they have been previously implicated in the pathogenesis of ADPKD. Immunoblotting was used to validate the proteomics results, confirming higher abundances of the selected proteins in ADPKD-uEVs in three independent groups of ADPKD-patients. While villin-1, periplakin and envoplakin were more abundant in advanced stages of the disease, complement was already higher in uEVs of young ADPKD patients with preserved renal function. Furthermore, all five proteins correlated positively with height adjusted total kidney volume. The proteins of interest were also analyzed in kidney tissues from kidney-specific-tamoxifen-inducible Pkd1-deletion mice, demonstrating higher expression in more severe stages of the disease. In summary, proteomic analysis of uEVs identified plakins and complement as disease-associated proteins in ADPKD. These proteins are new candidates for evaluation as biomarkers or targets for therapy in ADPKD.

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