Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease
Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022006110 |
| _version_ | 1797384167042842624 |
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| author | Ikhlak Ahmed Mubarak Ziab Sahar Da’as Waseem Hasan Sujitha P. Jeya Elbay Aliyev Sabah Nisar Ajaz A. Bhat Khalid Adnan Fakhro Ammira S. Alshabeeb Akil |
| author_facet | Ikhlak Ahmed Mubarak Ziab Sahar Da’as Waseem Hasan Sujitha P. Jeya Elbay Aliyev Sabah Nisar Ajaz A. Bhat Khalid Adnan Fakhro Ammira S. Alshabeeb Akil |
| author_sort | Ikhlak Ahmed |
| collection | DOAJ |
| description | Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology. In this study, we performed a meta-analysis on the expression profiles of GSE1009, GSE30122, GSE96804, GSE99340, GSE104948, GSE104954, and GSE111154 to identify critical transcriptional factors associated with DN progression. The analysis was conducted for all individual datasets for each kidney tissue (glomerulus, tubules, and kidney cortex). We identified distinct clusters of susceptibility genes that were dysregulated in a renal compartment-specific pattern. Further, we recognized a small but a closely connected set of these susceptibility genes enriched for podocyte differentiation, several of which were characterized as genes encoding critical transcriptional factors (TFs) involved in DN development and podocyte function. To validate the role of identified TFs in DN progression, we functionally validated the three main TFs (DACH1, LMX1B, and WT1) identified through differential gene expression and network analysis using the hyperglycemic zebrafish model. We report that hyperglycemia-induced altered gene expression of the key TF genes leads to morphological abnormalities in zebrafish glomeruli, pronephric tubules, proximal and distal ducts. This study demonstrated that altered expression of these TF genes could be associated with hyperglycemia-induced nephropathy and, thus, aids in understanding the molecular drivers, essential genes, and pathways that trigger DN initiation and development. |
| first_indexed | 2024-03-08T21:31:33Z |
| format | Article |
| id | doaj.art-bd0133a9a17947bf80d7fa77cc7f8d82 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T21:31:33Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-bd0133a9a17947bf80d7fa77cc7f8d822023-12-21T07:30:41ZengElsevierComputational and Structural Biotechnology Journal2001-03702023-01-0121716730Network-based identification and prioritization of key transcriptional factors of diabetic kidney diseaseIkhlak Ahmed0Mubarak Ziab1Sahar Da’as2Waseem Hasan3Sujitha P. Jeya4Elbay Aliyev5Sabah Nisar6Ajaz A. Bhat7Khalid Adnan Fakhro8Ammira S. Alshabeeb Akil9Department of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarZebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarZebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarHuman Genetics Department, Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar; Department of Genetic Medicine, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar; Human Genetics Department, Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, QatarDepartment of Human Genetics-Precision Medicine in Diabetes Prevention, Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Human Genetics Department, Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar; Correspondence to: Precision Medicine of Diabetes, Obesity and Cancer Research Program, Human Genetics Department, Sidra Medicine, PO Box 26999, Doha, Qatar.Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology. In this study, we performed a meta-analysis on the expression profiles of GSE1009, GSE30122, GSE96804, GSE99340, GSE104948, GSE104954, and GSE111154 to identify critical transcriptional factors associated with DN progression. The analysis was conducted for all individual datasets for each kidney tissue (glomerulus, tubules, and kidney cortex). We identified distinct clusters of susceptibility genes that were dysregulated in a renal compartment-specific pattern. Further, we recognized a small but a closely connected set of these susceptibility genes enriched for podocyte differentiation, several of which were characterized as genes encoding critical transcriptional factors (TFs) involved in DN development and podocyte function. To validate the role of identified TFs in DN progression, we functionally validated the three main TFs (DACH1, LMX1B, and WT1) identified through differential gene expression and network analysis using the hyperglycemic zebrafish model. We report that hyperglycemia-induced altered gene expression of the key TF genes leads to morphological abnormalities in zebrafish glomeruli, pronephric tubules, proximal and distal ducts. This study demonstrated that altered expression of these TF genes could be associated with hyperglycemia-induced nephropathy and, thus, aids in understanding the molecular drivers, essential genes, and pathways that trigger DN initiation and development.http://www.sciencedirect.com/science/article/pii/S2001037022006110Diabetic nephropathyDiabetic kidney diseaseGene expressionNetwork analysisHyperglycemic zebrafishTranscription factors |
| spellingShingle | Ikhlak Ahmed Mubarak Ziab Sahar Da’as Waseem Hasan Sujitha P. Jeya Elbay Aliyev Sabah Nisar Ajaz A. Bhat Khalid Adnan Fakhro Ammira S. Alshabeeb Akil Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease Computational and Structural Biotechnology Journal Diabetic nephropathy Diabetic kidney disease Gene expression Network analysis Hyperglycemic zebrafish Transcription factors |
| title | Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| title_full | Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| title_fullStr | Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| title_full_unstemmed | Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| title_short | Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| title_sort | network based identification and prioritization of key transcriptional factors of diabetic kidney disease |
| topic | Diabetic nephropathy Diabetic kidney disease Gene expression Network analysis Hyperglycemic zebrafish Transcription factors |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022006110 |
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