- Kunkle, B; Felty, Q; Narasimhan, G; Trevino, F; Roy, D
- The objective of this study was to use Oncomine (a database of DNA microarrays) to identifies NRF1, Tfam and Myc co-expressed genes and their possible implication in childhood brain tumor (CBT) development through controlling mitochondrial biogenesis. A meta-analysis was performed on several microarray studies on brain cancer found within Oncomine. The three main target genes of the meta-analysis were: V-myc myelocytomatosis viral oncogene homolog (avian) (Myc), Tfam: transcription factor A, mitochondrial (mt) (Tfam), and nuclear respiratory factor-1 (NRF1), that are involved in the mitochondrial biogenesis. For the Myc and Tfam meta-analysis we selected 5 studies having co-expression of brain data for Tfam; these same studies were selected for Myc. The meta-analysis included 5 studies with a total of 111 microarrays. A total of 208 coexpressed Myc genes with a significance of 40%+ (significant in 2 of 5 studies) and 206 co-expressed Tfam genes with significance of 40%+ were identified. 9 significant genes overlapped between Myc and Tfam: ALCAM, BMP2, CALCRL, CDH11, DUSP4, EMP1, SMAD3, SNAP23, and UBE2D1. A program called FuncAssociate was used to perform GO Term Enrichment analysis to obtain characteristics of the set of significant genes for both Tfam and Myc. The top GO Term for Myc was 'Phosphoribosylamine-glycine ligase activity'. The function of this GO Term is the Catalysis of the reaction: ATP + 5-phospho-D-ribosylamine + glycine = ADP + phosphate + N1-(5-phospho-D-ribosyl)glycine. Interestingly, this is part of the electron transport chain and thus mitochondrial biogenesis. The top GO Term for Tfam was 'Peptide-aspartate beta-dioxygenase activity'. This functions in the catalysis of the reaction: peptide L-aspartate + 2-oxoglutarate + O2 = peptide 3-hydroxy-L-aspartate + succinate + CO2. We expanded the meta-analysis to include NRF1 which also controls mitochondrial biogenesis via regulating Tfam. Interestingly, this gene has the same promoter recognition sequence as Myc . This meta-analysis, which combined 33 microarrays from two different studies, identified 26 genes co-expressed by all three genes (NRF1, Tfam, and Myc). Of these genes, three were found to be significantly co-expressed in the original metaanalysis of Tfam and myc. They were SMAD3, SNAP23 and UBE2D1. This study was able to identify a set of genes significantly correlated with NRF1, Myc and Tfam that control mitochondrial biogenesis. Furthermore, it identified 9 possible pathway partners of Myc and Tfam and a number of functions enriched in Myc, Tfam, and NRF1 in brain tumors. Since NRF1, Myc and Tfam genes play a large part in both brain development and mitochondrial biogenesis, the identification of co-expressed genes in similar pathways of these three mitochondrial biogenesis controlling genes could be key in elucidating how dysfunction of mitochondrial signaling may be involved in the development of childhood brain tumors.
- December 1, 2009
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