Mitochondrial and Nuclear Genomic Responses to Loss of LRPPRC Expression
| Autor: | Vamsi K. Mootha, Biao Luo, David E. Root, Vishal M. Gohil, Casey A. Belcher-Timme, Roland Nilsson |
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| Rok vydání: | 2010 |
| Předmět: |
Mitochondrial DNA
Nuclear gene Genomics and Proteomics Leigh Syndrome French-Canadian type Computational biology Microarray Biology DNA Mitochondrial Models Biological Biochemistry Glycosphingolipids Pathogenesis Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Metabolic Diseases RNA interference Humans Gene silencing Gene Silencing RNA Messenger Allele Molecular Biology Gene Cell Line Transformed Hexoses 030304 developmental biology Regulation of gene expression Genetics 0303 health sciences Gene knockdown Mitochondrial Metabolism Gene Expression Profiling Molecular Bases of Disease Cell Biology Neoplasm Proteins LRPPRC Gene expression profiling Gene Expression Regulation Mutation Prostaglandins Molecular Medicine Additions and Corrections Leigh Disease RNA Interference (RNAi) Function (biology) 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Rapid advances in genotyping and sequencing technology have dramatically accelerated the discovery of genes underlying human disease. Elucidating the function of such genes and understanding their role in pathogenesis, however, remain challenging. Here, we introduce a genomic strategy to characterize such genes functionally, and we apply it to LRPPRC, a poorly studied gene that is mutated in Leigh syndrome, French-Canadian type (LSFC). We utilize RNA interference to engineer an allelic series of cellular models in which LRPPRC has been stably silenced to different levels of knockdown efficiency. We then combine genome-wide expression profiling with gene set enrichment analysis to identify cellular responses that correlate with the loss of LRPPRC. Using this strategy, we discovered a specific role for LRPPRC in the expression of all mitochondrial DNA-encoded mRNAs, but not the rRNAs, providing mechanistic insights into the enzymatic defects observed in the disease. Our analysis shows that nuclear genes encoding mitochondrial proteins are not collectively affected by the loss of LRPPRC. We do observe altered expression of genes related to hexose metabolism, prostaglandin synthesis, and glycosphingolipid biology that may either play an adaptive role in cell survival or contribute to pathogenesis. The combination of genetic perturbation, genomic profiling, and pathway analysis represents a generic strategy for understanding disease pathogenesis. |
| Databáze: | OpenAIRE |
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