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Comparative analysis of cis-regulation following stroke and seizures in subspaces of conserved eigensystems.

Dabrowski M, Dojer N, Zawadzka M, Mieczkowski J, Kaminska B - BMC Syst Biol (2010)

Bottom Line: It is often desirable to separate effects of different regulators on gene expression, or to identify effects of the same regulator across several systems.We identified a novel antagonistic effect of the motif recognized by the nuclear matrix attachment region-binding protein Satb1 on AP1-driven transcriptional activation, suggesting a link between chromatin loop structure and gene activation by AP1.The effects of motifs binding Satb1 and Creb on gene expression in brain conform to the assumption of the linear response model of gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland. m.dabrowski@nencki.gov.pl

ABSTRACT

Background: It is often desirable to separate effects of different regulators on gene expression, or to identify effects of the same regulator across several systems. Here, we focus on the rat brain following stroke or seizures, and demonstrate how the two tasks can be approached simultaneously.

Results: We applied SVD to time-series gene expression datasets from the rat experimental models of stroke and seizures. We demonstrate conservation of two eigensystems, reflecting inflammation and/or apoptosis (eigensystem 2) and neuronal synaptic activity (eigensystem 3), between the stroke and seizures. We analyzed cis-regulation of gene expression in the subspaces of the conserved eigensystems. Bayesian networks analysis was performed separately for either experimental model, with cross-system validation of the highest-ranking features. In this way, we correctly re-discovered the role of AP1 in the regulation of apoptosis, and the involvement of Creb and Egr in the regulation of synaptic activity-related genes. We identified a novel antagonistic effect of the motif recognized by the nuclear matrix attachment region-binding protein Satb1 on AP1-driven transcriptional activation, suggesting a link between chromatin loop structure and gene activation by AP1. The effects of motifs binding Satb1 and Creb on gene expression in brain conform to the assumption of the linear response model of gene regulation. Our data also suggest that numerous enhancers of neuronal-specific genes are important for their responsiveness to the synaptic activity.

Conclusion: Eigensystems conserved between stroke and seizures separate effects of inflammation/apoptosis and neuronal synaptic activity, exerted by different transcription factors, on gene expression in rat brain.

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Functional Gene Ontology annotations associated with the conserved eigensystems (A-D) Association of loadings of the conserved eigensystems with the functional annotations from the GO "biological process" ontology were analyzed by Wilcoxon sign rank test using RankGOstat [55]. Twenty GO terms most associated with a given eigensystem, and their association FDR q-values are shown as bar plots. For the plots the q-values were log10-transformed and multiplied by +1 or -1, to reflect association with the positive or negative loadings of a particular eigensystem. GO terms with overlapping meanings (identified by human inspection) are indicated by the same colour of the bars, with red marking terms related to "synaptic transmission", blue marking terms similar to "inflammatory response", and black marking terms describing cell death/apoptosis.
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Figure 3: Functional Gene Ontology annotations associated with the conserved eigensystems (A-D) Association of loadings of the conserved eigensystems with the functional annotations from the GO "biological process" ontology were analyzed by Wilcoxon sign rank test using RankGOstat [55]. Twenty GO terms most associated with a given eigensystem, and their association FDR q-values are shown as bar plots. For the plots the q-values were log10-transformed and multiplied by +1 or -1, to reflect association with the positive or negative loadings of a particular eigensystem. GO terms with overlapping meanings (identified by human inspection) are indicated by the same colour of the bars, with red marking terms related to "synaptic transmission", blue marking terms similar to "inflammatory response", and black marking terms describing cell death/apoptosis.

Mentions: In both experimental models, the positive loading of the second eigensystem was significantly associated with overlapping GO terms describing the inflammatory response to the brain injury (Figure 3A, B). Additionally, in the MCAO system the positive loading of eigensystem M2 was also significantly associated with GO terms describing programmed cell death (apoptosis).


Comparative analysis of cis-regulation following stroke and seizures in subspaces of conserved eigensystems.

Dabrowski M, Dojer N, Zawadzka M, Mieczkowski J, Kaminska B - BMC Syst Biol (2010)

Functional Gene Ontology annotations associated with the conserved eigensystems (A-D) Association of loadings of the conserved eigensystems with the functional annotations from the GO "biological process" ontology were analyzed by Wilcoxon sign rank test using RankGOstat [55]. Twenty GO terms most associated with a given eigensystem, and their association FDR q-values are shown as bar plots. For the plots the q-values were log10-transformed and multiplied by +1 or -1, to reflect association with the positive or negative loadings of a particular eigensystem. GO terms with overlapping meanings (identified by human inspection) are indicated by the same colour of the bars, with red marking terms related to "synaptic transmission", blue marking terms similar to "inflammatory response", and black marking terms describing cell death/apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902439&req=5

Figure 3: Functional Gene Ontology annotations associated with the conserved eigensystems (A-D) Association of loadings of the conserved eigensystems with the functional annotations from the GO "biological process" ontology were analyzed by Wilcoxon sign rank test using RankGOstat [55]. Twenty GO terms most associated with a given eigensystem, and their association FDR q-values are shown as bar plots. For the plots the q-values were log10-transformed and multiplied by +1 or -1, to reflect association with the positive or negative loadings of a particular eigensystem. GO terms with overlapping meanings (identified by human inspection) are indicated by the same colour of the bars, with red marking terms related to "synaptic transmission", blue marking terms similar to "inflammatory response", and black marking terms describing cell death/apoptosis.
Mentions: In both experimental models, the positive loading of the second eigensystem was significantly associated with overlapping GO terms describing the inflammatory response to the brain injury (Figure 3A, B). Additionally, in the MCAO system the positive loading of eigensystem M2 was also significantly associated with GO terms describing programmed cell death (apoptosis).

Bottom Line: It is often desirable to separate effects of different regulators on gene expression, or to identify effects of the same regulator across several systems.We identified a novel antagonistic effect of the motif recognized by the nuclear matrix attachment region-binding protein Satb1 on AP1-driven transcriptional activation, suggesting a link between chromatin loop structure and gene activation by AP1.The effects of motifs binding Satb1 and Creb on gene expression in brain conform to the assumption of the linear response model of gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland. m.dabrowski@nencki.gov.pl

ABSTRACT

Background: It is often desirable to separate effects of different regulators on gene expression, or to identify effects of the same regulator across several systems. Here, we focus on the rat brain following stroke or seizures, and demonstrate how the two tasks can be approached simultaneously.

Results: We applied SVD to time-series gene expression datasets from the rat experimental models of stroke and seizures. We demonstrate conservation of two eigensystems, reflecting inflammation and/or apoptosis (eigensystem 2) and neuronal synaptic activity (eigensystem 3), between the stroke and seizures. We analyzed cis-regulation of gene expression in the subspaces of the conserved eigensystems. Bayesian networks analysis was performed separately for either experimental model, with cross-system validation of the highest-ranking features. In this way, we correctly re-discovered the role of AP1 in the regulation of apoptosis, and the involvement of Creb and Egr in the regulation of synaptic activity-related genes. We identified a novel antagonistic effect of the motif recognized by the nuclear matrix attachment region-binding protein Satb1 on AP1-driven transcriptional activation, suggesting a link between chromatin loop structure and gene activation by AP1. The effects of motifs binding Satb1 and Creb on gene expression in brain conform to the assumption of the linear response model of gene regulation. Our data also suggest that numerous enhancers of neuronal-specific genes are important for their responsiveness to the synaptic activity.

Conclusion: Eigensystems conserved between stroke and seizures separate effects of inflammation/apoptosis and neuronal synaptic activity, exerted by different transcription factors, on gene expression in rat brain.

Show MeSH
Related in: MedlinePlus