Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy

Cell Metabolism, Год журнала: 2024, Номер 36(5), С. 1105 - 1125.e10

Опубликована: Март 20, 2024

A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct anatomical regions. We generated transcriptomes of 446,267 cells chromatin accessibility profiles 401,875 developed a package analyze 408,218 metabolomes. find the same cell type, including thin limb, thick ascending limb loop Henle principal cells, display transcriptomic, accessibility, metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene revealed non-overlapping metabolic signatures between nephron segments dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating omics with clinical data identified PLEKHA1 as disease marker, its vitro knockdown increased expression PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying anatomy.

Язык: Английский

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Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 12, 2024

Abstract Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured fails to undergo normal and assumes proinflammatory profibrotic phenotype that may promote fibrosis chronic kidney disease. The healthy failed change is marked by cell state-specific transcriptomic epigenomic changes. Single nucleus joint RNA- ATAC-seq sequencing offers an opportunity study the gene regulatory networks underpinning these changes in order identify key drivers. We develop regularized regression approach construct genome-wide parametric using multiomic datasets. generate single dataset from seven adult human samples apply our method drivers injury response associated with demonstrate highly effective tool for predicting cis- trans- elements transition use it NFAT5 as driver maladaptive state.

Язык: Английский

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Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Янв. 29, 2024

Abstract Background Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY present kidney increases with age chronic disease. Results The likelihood a cell having varies depending on its location nephron. Cortical epithelial types have greater proportion than medullary or glomerular types, which may reflect their proliferative history. Proximal tubule cells are abundant type cortex susceptible hypoxic injury. A subset these acquires pro-inflammatory transcription chromatin accessibility profile associated expression HAVCR1 , VCAM1 PROM1 . These injured greatest presence predicts future function decline. Moreover, proximal more likely harbor additional large gains express pro-survival pathways. Spatial transcriptomics localizes pro-fibrotic microenvironment where they adopt secretory phenotype communicate infiltrating immune cells. Conclusions We hypothesize an indicator increased DNA damage potential marker cellular senescence can be applied datasets other tissues.

Язык: Английский

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Spatially resolved genome-wide joint profiling of epigenome and transcriptome with spatial-ATAC-RNA-seq and spatial-CUT&Tag-RNA-seq

Nature Protocols, Год журнала: 2025, Номер unknown

Опубликована: Март 21, 2025

Язык: Английский

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Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids

Journal of the American Society of Nephrology, Год журнала: 2023, Номер 34(10), С. 1672 - 1686

Опубликована: Июль 25, 2023

HNF4 genes promote proximal tubule differentiation in mice, but their function human nephrogenesis is not fully defined. This study uses pluripotent stem cell (PSC)-derived kidney organoids as a model to investigate HNF4A and HNF4G functions. The loss of , impaired reabsorption-related molecule expression microvilli formation tubules. Cleavage under targets release using nuclease (CUT&RUN) sequencing CRISPR-mediated transcriptional activation (CRISPRa) further confirm that directly regulates its target genes. Human provide good for studying regulation development.

Язык: Английский

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Epigenetic reprogramming driving successful and failed repair in acute kidney injury

Science Advances, Год журнала: 2024, Номер 10(32)

Опубликована: Авг. 7, 2024

Acute kidney injury (AKI) causes epithelial damage followed by subsequent repair. While successful repair restores function, this process is often incomplete and can lead to chronic disease (CKD) in a called failed To better understand the epigenetic reprogramming driving AKI-to-CKD transition, we generated single-nucleus multiomic atlas for full mouse AKI time course, consisting of ~280,000 transcriptomes epigenomes. We reveal cell-specific dynamic alterations gene regulatory landscapes reflecting, especially, activation proinflammatory pathways. further data from four human samples including validation genome-wide identification nuclear factor κB binding sites. A regularized regression analysis identifies key regulators involved both cell fate, identifying transcription CREB5 as regulator tubular that also drives proximal proliferation after injury. Our interspecies approach provides foundation comprehensively states AKI.

Язык: Английский

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Segment specific loss of NFAT5 function in the kidneys is sufficient to induce a global kidney injury like phenotype

The FASEB Journal, Год журнала: 2025, Номер 39(2)

Опубликована: Янв. 28, 2025

Abstract Nuclear factor of activated T‐cells 5 (NFAT5) is a transcription known for its role in osmotic stress adaptation the renal inner medulla, due to gradient that generated between cortex and medulla. However, broader implications kidney injury chronic disease (CKD) are less understood. Here we used two different Cre deleter mice (Ksp1.3‐Cre Aqp2‐Cre) generate tubule segment even cell type‐specific NFAT5‐deficient performed extensive gene expression profiling. In both Nfat5 knockout models, observed massive changes pattern, with heightened inflammatory responses injury, culminating fibrosis. Interestingly, were much more prominent Aqp2Cre +/− fl/fl lack NFAT5 only collecting duct. By analyzing medullary cortical regions separately, confirmed loss results extends beyond hypertonic areas. Renal correlates level genes involved response, severity, cytokine signaling. Thus, essential not adapting but also function, which induces activation response signaling might affect functional expression.

Язык: Английский

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Injured proximal tubular epithelial cells lose HNF4A expression crucial for brush border formation and transport

American Journal Of Pathology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Sodium-glucose cotransporter 2 inhibitors: a novel approach to prevent the transition from acute kidney injury to chronic kidney disease

Current Opinion in Nephrology & Hypertension, Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

Purpose of review Acute kidney injury (AKI) often progresses to chronic disease (CKD), yet standardized clinical guidelines for managing this transition remain lacking. Recent studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) or flozins improve AKI outcomes. Studies on patients living with diabetes post-AKI show reduce mortality, CKD progression, and recurrent AKI, highlighting their potential in mitigating maladaptive repair. We discuss recent preclinical evidence supporting a role SGLT2i during repair subsequent CKD. findings is characterized by endothelial tubular injury, hypoperfusion, metabolic dysfunction, inflammation, cell death. restore renal hemodynamics, mitochondrial oxidative stress, improving recovery following AKI. Additionally, mitigate death counteracting apoptosis ferroptosis while reducing inflammation through suppression pro-inflammatory cytokines inflammasome activation. Beyond exhibit long-term antifibrotic effects, extracellular matrix deposition even after treatment discontinuation. Preclinical demonstrate sustained protective effect integrity months short-term treatment. Summary These hold promise broad nephroprotection, robust biological rationale Further research needed optimize use establish management both diabetic nondiabetic populations.

Язык: Английский

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PETScan: Score-Based Genome-Wide Association Analysis of RNA-Seq and ATAC-Seq Data

Опубликована: Апрель 17, 2025

Abstract High-dimensional sequencing data, such as RNA-Seq for gene expression and ATAC-Seq chromatin accessibility, are widely used in studying systems biology. Accessible allows transcription factors regulatory elements to bind DNA, thereby regulating through the activation or repression of target genes. The association analysis data provides insights into mechanisms. Most existing analytic tools exclusively focus on cis-associations, despite being able physically interact with distant Furthermore, conventional approaches often utilize Pearson Spearman correlations, which ignore count-based nature data. To address these limitations, we introduce PETScan , a computationally efficient genome-wide PE ak- T ranscript Sc ore-based an alysis, utilizing negative binomial models better accommodate We leverage score tests matrix calculations improved computational efficiency, combine empirical permutation method genomic control ensure valid p-value studies limited sample sizes. In real-world datasets, achieved three orders magnitude faster than Wald tests, while identifying similar significant gene-peak pairs. R package is available GitHub at https://github.com/yajing-hao/PETScan .

Язык: Английский

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