Abstract
BackgroundAlterations in brain-derived neurotrophic factor (BDNF) gene expression contribute to serious pathologies such as depression, epilepsy, cancer, Alzheimer's, Huntington and Parkinson's disease. Therefore, exploring the mechanisms of BDNF regulation represents a great clinical importance. Studying BDNF expression remains difficult due to its multiple neural activity-dependent and tissue-specific promoters. Thus, microarray data could provide insight into the regulation of this complex gene. Conventional microarray co-expression analysis is usually carried out by merging the datasets or by confirming the re-occurrence of significant correlations across datasets. However, co-expression patterns can be different under various conditions that are represented by subsets in a dataset. Therefore, assessing co-expression by measuring correlation coefficient across merged samples of a dataset or by merging datasets might not capture all correlation patterns.ResultsIn our study, we performed meta-coexpression analysis of publicly available microarray data using BDNF as a "guide-gene" introducing a "subset" approach. The key steps of the analysis included: dividing datasets into subsets with biologically meaningful sample content (e.g. tissue, gender or disease state subsets); analyzing co-expression with the BDNF gene in each subset separately; and confirming co- expression links across subsets. Finally, we analyzed conservation in co-expression with BDNF between human, mouse and rat, and sought for conserved over-represented TFBSs in BDNF and BDNF-correlated genes. Correlated genes discovered in this study regulate nervous system development, and are associated with various types of cancer and neurological disorders. Also, several transcription factor identified here have been reported to regulate BDNF expression in vitro and in vivo.ConclusionThe study demonstrates the potential of the "subset" approach in co-expression conservation analysis for studying the regulation of single genes and proposes novel regulators of BDNF gene expression.
Highlights
Alterations in brain-derived neurotrophic factor (BDNF) gene expression contribute to serious pathologies such as depression, epilepsy, cancer, Alzheimer's, Huntington and Parkinson's disease
The study demonstrates the potential of the "subset" approach in co-expression conservation analysis for studying the regulation of single genes and proposes novel regulators of BDNF gene expression
Based on MW test results [see Additional file 12: The results of Mann-Whitney tests (CONFAC)], on the Importance score [see Additional file 10: DiRE motif discovery results for BDNF and 84 conserved correlated genes] and on the conservation data (UCSC), we propose potential regulators of BDNF (Figure 3 and Table 3) [see Additional file 13: Highly conserved TFBSs in the BDNF gene]
Summary
Alterations in brain-derived neurotrophic factor (BDNF) gene expression contribute to serious pathologies such as depression, epilepsy, cancer, Alzheimer's, Huntington and Parkinson's disease. Studying BDNF expression remains difficult due to its multiple neural activitydependent and tissue-specific promoters. Publicly available microarray data provide information on human genome-wide gene expression under various experimental conditions, which for most researchers would be difficult to access otherwise. Alterations in BDNF expression can contribute to serious pathologies such as epilepsy, Huntington, Alzheimer's, and Parkinson's disease [6]. Numerous studies have been conducted to unravel the regulation of BDNF expression in rodents and human. Unraveling the regulation of BDNF expression remains difficult due to its multiple activitydependent and tissue-specific promoters. Analysis of the gene expression under various experimental conditions using microarray data could provide insight into the regulation of this complex gene
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