Genome-wide expression analysis in a Fabry disease human podocyte cell line

Sarah Snanoudj; Céline Derambure; Cheng Zhang; Nguyen Thi Hai Yen; Céline Lesueur; Sophie Coutant; Lénaïg Abily-Donval; Stéphane Marret; Hong Yang; Adil Mardinoglu; Soumeya Bekri; Abdellah Tebani

doi:10.1016/j.heliyon.2024.e34357

Genome-wide expression analysis in a Fabry disease human podocyte cell line

Sarah Snanoudj, Céline Derambure, Cheng Zhang, Nguyen Thi Hai Yen, Céline Lesueur, Sophie Coutant, Lénaïg Abily-Donval, Stéphane Marret, Hong Yang, Adil Mardinoglu, Soumeya Bekri, Abdellah Tebani^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.

Original language	English
Article number	e34357
Journal	Heliyon
Volume	10
Issue number	14
Early online date	9 Jul 2024
DOIs	https://doi.org/10.1016/j.heliyon.2024.e34357
Publication status	Published - 30 Jul 2024

Keywords

Fabry disease
Metabolic modeling
Podocyte
RNAseq
Systems biology
Transcriptomics

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Genome-wide expression analysis_SNANOUDJ_Publishedonline9July2024_GOLD_VoR (CC BY)Final published version, 6.66 MBLicence: CC BY

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title = "Genome-wide expression analysis in a Fabry disease human podocyte cell line",

abstract = "Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.",

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doi = "10.1016/j.heliyon.2024.e34357",

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AU - Snanoudj, Sarah

AU - Derambure, Céline

AU - Zhang, Cheng

AU - Hai Yen, Nguyen Thi

AU - Lesueur, Céline

AU - Coutant, Sophie

AU - Abily-Donval, Lénaïg

AU - Marret, Stéphane

AU - Yang, Hong

AU - Mardinoglu, Adil

AU - Bekri, Soumeya

AU - Tebani, Abdellah

PY - 2024/7/30

Y1 - 2024/7/30

N2 - Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.

AB - Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.

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KW - Metabolic modeling

KW - Podocyte

KW - RNAseq

KW - Systems biology

KW - Transcriptomics

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SN - 2405-8440

VL - 10

JO - Heliyon

JF - Heliyon

IS - 14

M1 - e34357

ER -

Genome-wide expression analysis in a Fabry disease human podocyte cell line

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