Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators
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Susanne Mende1, Loic Royer, Alexander Herr
1Department of Neurology, Dresden University of Technology, Germany.
Background:
The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation.
Objective:
To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome.
Methods:
Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses.
Results:
Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1 complex, nuclear factor Y and cAMP responsive element-binding protein-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction.
Discussion:
Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome.
Insights
The mitochondrial DNA (mtDNA) mutation A3243G causes MELAS syndrome. This study identified novel gene regulators and networks, offering new therapeutic targets for this mitochondrial disease.
Area of Science:
- Genomics and Molecular Biology
- Mitochondrial Medicine
- Systems Biology
Background:
- The A3243G mutation in mitochondrial DNA (mtDNA) is a frequent cause of MELAS syndrome.
- Nuclear gene expression reprogramming is crucial for adapting cellular processes to mitochondrial dysfunction in MELAS.
- This adaptation may explain the diverse clinical presentations of MELAS.
Purpose of the Study:
- To identify master regulatory protein networks in MELAS syndrome.
- To discover disease-modifying genes associated with MELAS.
- To understand the nuclear gene expression response to mtDNA mutations.
Main Methods:
- Analysis of whole blood transcriptomes from 10 MELAS patients.
- Integration of Affymetrix microarray data with regulatory and protein interaction network analyses.
- Hierarchical cluster and correlation analyses of gene expression and clinical data.
Main Results:
- Mutant mtDNA load significantly influences nuclear gene expression patterns.
- Novel master regulators, including HIF-1, NF-Y, and CREB-related factors, were identified.
- Disease-modifying genes impacting MELAS phenotype are linked to nucleic acid/protein metabolism and signal transduction, not solely energy metabolism.
Conclusions:
- The study provides a framework for exploring new pathogenetic mechanisms in MELAS.
- Identified regulatory networks and genes offer potential therapeutic targets.
- Understanding nuclear-mitochondrial cross-talk is key to developing MELAS treatments.
