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In silico nano-dissection: defining cell type specificity at transcriptional level in human disease (glomeruli)

ABSTRACT: To identify genes with cell-lineage-specific expression not accessible by experimental micro-dissection, we developed a genome-scale iterative method, in-silico nano-dissection, which leverages high-throughput functional-genomics data from tissue homogenates using a machine-learning framework. This study applied nano-dissection to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary proteinuric syndromes and acquired CKD. In-silico prediction accuracy exceeded predictions derived from fluorescence-tagged-murine podocytes, identified genes recently implicated in hereditary glomerular disease and predicted genes significantly correlated with kidney function. The nano-dissection method is broadly applicable to define lineage specificity in many functional and disease contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47183 | GEO | 2013/08/06

SECONDARY ACCESSION(S): PRJNA205044

REPOSITORIES: GEO

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In silico nano-dissection: defining cell type specificity at transcriptional level in human disease (glomeruli)

Project description:To identify genes with cell-lineage-specific expression not accessible by experimental micro-dissection, we developed a genome-scale iterative method, in-silico nano-dissection, which leverages high-throughput functional-genomics data from tissue homogenates using a machine-learning framework. This study applied nano-dissection to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary proteinuric syndromes and acquired CKD. In-silico prediction accuracy exceeded predictions derived from fluorescence-tagged-murine podocytes, identified genes recently implicated in hereditary glomerular disease and predicted genes significantly correlated with kidney function. The nano-dissection method is broadly applicable to define lineage specificity in many functional and disease contexts. We applied a machine-learning framework on high-throughput gene expression data from human kidney biopsy tissue homogenates and predict novel podocyte-specific genes. The prediction was validated by Human Protein Atlas at protein level. Prediction accuracy was compared with predictions derived from experimental approach using fluorescence-tagged-murine podocytes.

2013-08-06 | E-GEOD-47183 | biostudies-arrayexpress

In silico nano-dissection: defining cell type specificity at transcriptional level in human disease (tubulointerstitium)

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In silico nano-dissection: defining cell type specificity at transcriptional level in human disease (tubulointerstitium)

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MYDGF Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease

Project description:Podocytes, highly differentiated glomerular epithelial cells, are essential for the maintenance of glomerular filtration barrier. Podocyte dysfunction in podocytes is a major determinant of proteinuric kidney disease. By RNA sequencing analysis in ADR-treated podocytes with or without MYDGF overexpression, we observed the significant changes of genes important in regulating cell cycle in podocytes with ADR treatment.

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Project description:We and others have previously shown that glomerular endothelial cells and podocytes express hypoxia-inducible transcription factors (HIFs). HIFs bind to hypoxia response elements in target genes, such as vascular endothelial growth factor, which is continually produced by podocytes throughout life. To further assess function of HIFs in podocyte biology, podocin-Cre mice were mated with floxed von Hippel-Lindau (VHL) mice to selectively delete VHL, a component of an E3 ligase complex responsible for degradation of HIFs in normoxia. We reasoned that cells lacking VHL would overexpress stable HIFs and upregulate hypoxia-responsive genes. Progeny from these crosses displayed two phenotypes, non-proteinuric with glomerular basement membrane (GBM) defects and proteinuric with GBM defects and end-stage renal failure at ~6 months of age. Gene changes associated with the mild, non-proteinuric phenotype were studied using isolated glomeruli from wildtype and Pod-Cre fVHL mice. At 4 weeks of age, urine was collected and urinary albumin was quantified by Albuwell elisa from Pod-Cre fVHL litters. At 6 weeks of age, glomeruli from 3 wildtype littermate controls and 3 non-proteinuric Pod-Cre fVHL mice were collected using the magnetic bead method. RNA was extracted and hybridized to Affymetrix microarrays.

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RNA expression data from glomeruli lacking von Hippel-Lindau protein in podocytes

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Project description:Podocytes are the highly specialised cells within the glomeruli of the kidney that maintain the filtration barrier by forming interdigitating foot processes and slit-diaphragms. Disruption to these features result in proteinuria. Studies into podocyte biology and disease has been hampered by a paucity of in vitro models of this non-proliferative cell type. Here we characterise sieved glomeruli from kidney organoids derived from human pluripotent stem cells. Compared to conditionally immortalised podocytes, organoid-derived glomeruli show superior podocyte-specific gene and protein expression, morphology and functional properties. Using CRISPR-derived MAFB reporter iPSC lines, homozygous MAFB mutant organoids recapitulated the anticipated disease related transcriptional changes. Culture of kidney organoids on chicken chorioallantoic membrane resulted in glomerular vascularisation, glomerular filtration barrier assembly, formation of slit diaphragms and fenestrated endothelial cells. This definitively demonstrates that human iPSC kidney organoid-derived glomeruli can serve as an accurate model of human podocytopathies and glomerular disease in vitro.

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Project description:The progression of proteinuric kidney disease is associated with podocyte loss but the mechanisms remain unclear. Podocytes reenter the cell cycle to repair damaged ds DNA breaks. However, unsuccessful repair results in podocytes crossing the G1/S checkpoint and undergoes abortive cytokinesis. In this study, we identified Pfn1 as a major contributor in maintaining glomerular integrity and its loss in mice results in severe proteinuria, and kidney failure due to podocyte mitotic catastrophe, characterized by abundant multinucleated cells. Reentry of podocytes were identified by using FUCCI-2aR mice, accompanying the alteration of cell-cycle associated proteins, such as P21, P53, Cyclin B, and Cyclin D. Podocyte-specific translating ribosome affinity purification (TRAP) and RNAseq revealed a reduction of Ribosomal RNA-processing protein 8 (Rrp8) and re-expression of Rrp8 partially rescued the in-vitro phenotype. Clinical analysis of patients with proteinuric kidney disease demonstrated multinucleated podocytes and reduced podocyte profilin1 in kidney tissue. These results suggest that profilin is indispensible in regulating podocyte cell cycle and its disruption contributes to podocyte loss through mitotic catastrophe.

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Human iPSC-derived glomeruli provide an advanced model to interrogate podocyte biology and accurately recapitulate podocytopathy

Project description:Podocytes are highly specialised cells within the glomeruli of the kidney that maintain the filtration barrier by forming interdigitating foot processes and slit-diaphragms. Disruption to these features result in proteinuria and glomerulosclerosis. Studies into podocyte biology and disease have previously relied on conditionally immortalised cell lines due to the non- proliferative nature of this cell type. Here we describe an advanced model to study both podocyte and glomerular biology using isolated glomeruli from kidney organoids derived from human pluripotent stem cells.

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