title: Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators.
abstract: 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.
  
  
  CONCLUSIONS
  Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome.
authors.affiliation: Department of Neurology, Dresden University of Technology, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mende
authors.forename: Loic
authors.initials: L
authors.lastname: Royer
authors.forename: Alexander
authors.initials: A
authors.lastname: Herr
authors.forename: Janet
authors.initials: J
authors.lastname: Schmiedel
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kostic
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeder
authors.forename: Heinz
authors.initials: H
authors.lastname: Reichmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
mesh_terms: D000328:Adult; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D017241:MELAS Syndrome / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D040081:Protein Array Analysis / Q000379:methods; D055815:Young Adult