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The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes.

McClelland S, Brennan GP, Dubé C, Rajpara S, Iyer S, Richichi C, Bernard C, Baram TZ - Elife (2014)

Bottom Line: Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked.Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels.Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.

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Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.These genes have been classified (‘binned’) into eight groups by increasing order of their NRSF binding frequency rank percentile. Hence, these genes might be categorized as low-binding frequency (A–C), mid-binding frequency (D–F), and high-binding frequency (G–H). Each graph shows enrichment plots comparing gene expression in KA-seizures vs controls in the presence of random ODNs. Please see Table 1, top, for the numeric values and parameters of the analyses.DOI:http://dx.doi.org/10.7554/eLife.01267.010
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fig8: Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.These genes have been classified (‘binned’) into eight groups by increasing order of their NRSF binding frequency rank percentile. Hence, these genes might be categorized as low-binding frequency (A–C), mid-binding frequency (D–F), and high-binding frequency (G–H). Each graph shows enrichment plots comparing gene expression in KA-seizures vs controls in the presence of random ODNs. Please see Table 1, top, for the numeric values and parameters of the analyses.DOI:http://dx.doi.org/10.7554/eLife.01267.010

Mentions: To further test this idea, we analyzed the array data using gene set enrichment analysis (GSEA, MIT Broad Institute) (Mootha et al., 2003; Subramanian et al., 2005). GSEA is a computational method that determines whether an a priori defined set of genes shows statistically significant, concordant differences between two experimental groups. Comparison of the control group to the seizures group for each binned gene set as described above resulted in a graphic representation depicting the GSEA-normalized Enrichment Scores (NES), obtained from the Broad Institute's molecular signature database (MSigDB), for each set of partitioned NRSE-containing genes (Figure 7D). The GSEA graphs are shown in Figure 8, and the analysis parameters, including false discovery rate [FDR] and family-wise error rates [FWER] are found in Table 1. The expression of three of these ‘bins’ (gene sets partitioned by binding frequency) was significantly enriched in the control group (i.e., repressed in the seizure group) when compared to the levels of enrichment of gene sets composed of random permutations of genes (FWER *p < 0.05). Notably, the three significantly enriched gene-sets were not composed of genes with the highest NRSF binding frequency; rather, they consisted of genes between the 37.5th and 75th binding frequency rank percentile (Figure 7D; Table 1; Figure 8). In addition, when binding-frequency binned GSEA was used to compare the control group to the KA-seizure group receiving the NRSE–ODN treatment (i.e., with blocked NRSF function), the three binned gene sets were no longer significantly different from those in the control group (Table 1).10.7554/eLife.01267.010Figure 8.Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.


The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes.

McClelland S, Brennan GP, Dubé C, Rajpara S, Iyer S, Richichi C, Bernard C, Baram TZ - Elife (2014)

Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.These genes have been classified (‘binned’) into eight groups by increasing order of their NRSF binding frequency rank percentile. Hence, these genes might be categorized as low-binding frequency (A–C), mid-binding frequency (D–F), and high-binding frequency (G–H). Each graph shows enrichment plots comparing gene expression in KA-seizures vs controls in the presence of random ODNs. Please see Table 1, top, for the numeric values and parameters of the analyses.DOI:http://dx.doi.org/10.7554/eLife.01267.010
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129437&req=5

fig8: Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.These genes have been classified (‘binned’) into eight groups by increasing order of their NRSF binding frequency rank percentile. Hence, these genes might be categorized as low-binding frequency (A–C), mid-binding frequency (D–F), and high-binding frequency (G–H). Each graph shows enrichment plots comparing gene expression in KA-seizures vs controls in the presence of random ODNs. Please see Table 1, top, for the numeric values and parameters of the analyses.DOI:http://dx.doi.org/10.7554/eLife.01267.010
Mentions: To further test this idea, we analyzed the array data using gene set enrichment analysis (GSEA, MIT Broad Institute) (Mootha et al., 2003; Subramanian et al., 2005). GSEA is a computational method that determines whether an a priori defined set of genes shows statistically significant, concordant differences between two experimental groups. Comparison of the control group to the seizures group for each binned gene set as described above resulted in a graphic representation depicting the GSEA-normalized Enrichment Scores (NES), obtained from the Broad Institute's molecular signature database (MSigDB), for each set of partitioned NRSE-containing genes (Figure 7D). The GSEA graphs are shown in Figure 8, and the analysis parameters, including false discovery rate [FDR] and family-wise error rates [FWER] are found in Table 1. The expression of three of these ‘bins’ (gene sets partitioned by binding frequency) was significantly enriched in the control group (i.e., repressed in the seizure group) when compared to the levels of enrichment of gene sets composed of random permutations of genes (FWER *p < 0.05). Notably, the three significantly enriched gene-sets were not composed of genes with the highest NRSF binding frequency; rather, they consisted of genes between the 37.5th and 75th binding frequency rank percentile (Figure 7D; Table 1; Figure 8). In addition, when binding-frequency binned GSEA was used to compare the control group to the KA-seizure group receiving the NRSE–ODN treatment (i.e., with blocked NRSF function), the three binned gene sets were no longer significantly different from those in the control group (Table 1).10.7554/eLife.01267.010Figure 8.Gene set enrichment analysis (GSEA, Broad Institute, MIT) curves of hippocampal NRSE-containing genes.

Bottom Line: Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked.Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels.Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.

Show MeSH
Related in: MedlinePlus