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Patterns of human gene expression variance show strong associations with signaling network hierarchy.

Komurov K, Ram PT - BMC Syst Biol (2010)

Bottom Line: Our analysis shows that this pattern of EV reflects functional centrality: proteins with highly specific signaling functions are modulated more frequently than those with highly central functions in the network, which is also consistent with previous studies on tissue-specific gene expression.Interestingly, these patterns of EV along the signaling network hierarchy have significant correlations with promoter architectures of respective genes.Our analyses suggest a generic systems level mechanism of regulation of the cellular signaling network at the transcriptional level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 7435 Fannin St, Houston, TX 77054, USA. kkomurov@mdanderson.org

ABSTRACT

Background: Understanding organizational principles of cellular networks is one of the central goals of systems biology. Although much has been learnt about gene expression programs under specific conditions, global patterns of expressional variation (EV) of genes and their relationship to cellular functions and physiological responses is poorly understood.

Results: To understand global principles of relationship between transcriptional regulation of human genes and their functions, we have leveraged large-scale datasets of human gene expression measurements across a wide spectrum of cell conditions. We report that human genes are highly diverse in terms of their EV; while some genes have highly variable expression pattern, some seem to be relatively ubiquitously expressed across a wide range of conditions. The wide spectrum of gene EV strongly correlates with the positioning of proteins within the signaling network hierarchy, such that, secreted extracellular receptor ligands and membrane receptors have the highest EV, and intracellular signaling proteins have the lowest EV in the genome. Our analysis shows that this pattern of EV reflects functional centrality: proteins with highly specific signaling functions are modulated more frequently than those with highly central functions in the network, which is also consistent with previous studies on tissue-specific gene expression. Interestingly, these patterns of EV along the signaling network hierarchy have significant correlations with promoter architectures of respective genes.

Conclusion: Our analyses suggest a generic systems level mechanism of regulation of the cellular signaling network at the transcriptional level.

Show MeSH
Pattern of EV along the signaling hierarchy. A) A visual depiction of the signaling hierarchy as defined in text and Methods. B) Network plots of the signaling hierarchy. Each layer corresponds to the corresponding layer in A. Node colors show EVexpo values of corresponding genes and lines indicate directed protein-protein interactions. C) Heatmap of enrichment p-values of each gene class as defined in Kim et al (2005) for genes in corresponding signaling hierarchy levels. Colors indicate negative log (base 10) of p-values as determined by hypergeometric distribution formula. D) Boxplots of EV values of RS level genes with class I, II and III promoters. P-values of difference were calculated by Wilcoxon rank sum test.
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Figure 3: Pattern of EV along the signaling hierarchy. A) A visual depiction of the signaling hierarchy as defined in text and Methods. B) Network plots of the signaling hierarchy. Each layer corresponds to the corresponding layer in A. Node colors show EVexpo values of corresponding genes and lines indicate directed protein-protein interactions. C) Heatmap of enrichment p-values of each gene class as defined in Kim et al (2005) for genes in corresponding signaling hierarchy levels. Colors indicate negative log (base 10) of p-values as determined by hypergeometric distribution formula. D) Boxplots of EV values of RS level genes with class I, II and III promoters. P-values of difference were calculated by Wilcoxon rank sum test.

Mentions: Based on the observations above, we reasoned that extracellular ligands for cellular transmembrane receptors may be more variable than their receptors, meaning that cells are more likely to modulate the expression levels of secreted factors rather than their receptors in response to extracellular cues. We compared EVs of genes annotated as "receptor binding" (GO:0005102), "growth factor activity" (GO:0008083) or "cytokine activity" (GO:0005125) and "extracellular space" (GO:0005615) (SF list, n = 269 genes) to those annotated as "transmembrane receptor activity" (GO:0004888), "receptor activity" (GO:0004872) and "plasma membrane" (GO:0005886) (GR list, n = 1038 genes) (see Additional file 11). Although EVs of both classes are significantly higher when compared to the rest of genes, EVs of the SF list are significantly higher than those of the GR list (see Figure 3B). We wanted to determine if EVs of genes involved in signal transduction reflect the hierarchical position of the corresponding signaling molecules within the signaling network. In order to answer this question, we compiled a comperehensive signaling network from online databases (5499 genes and ~22,000 interactions, see Methods), and defined 5 levels of signaling hierarchy based on the positions of the signaling molecules (Figure 3A). The first level, growth factor modulators (GM class), are secreted molecules that modulate the activities of receptor-binding secreted factors. This class includes genes such as SFRP2 (Secreted Frizzled-Related Protein 2, regulator of WNT proteins), MMP1 (matrix metaloprotease 1, regulator of various growth factors/cytokines), IGFBP1 (IGF binding protein 1) and LTBP1 (latent TGF-beta binding protein). The next two levels are secreted factors (SF) and receptors (GR), explained above. Receptor substrates (RS) are molecules immediately downstream of receptors (GR), such as G-proteins (GNA genes), receptor-associated kinases (e.g. IRAK genes, ADRBK2, JAK1), and adaptor proteins (e.g. GRB2, SOS1-2, FADD, IRS1) among others; and the next class are molecules that mediate signal transduction downstream of RS (RS2) (see Methods). Strikingly, EV patterns of these levels display a gradient, with the GM level being the most variable, and RS being the least variable among these hierarchy levels (Figure 3B). This pattern is also reproduced with EVCK values (Additional file 10). This suggests that transcriptional regulation of intracellular signaling pathways mostly happens at the level of secreted growth factor modulators and growth factors, while signaling molecules immediately downstream of signaling receptors seem to be the least transcriptionally modulated. Accordingly, the RS and RS2 levels are mostly found in class I through III of genes based on their PIC occupancy, while GM, SF and GR levels are in class IV (Figure 3C).


Patterns of human gene expression variance show strong associations with signaling network hierarchy.

Komurov K, Ram PT - BMC Syst Biol (2010)

Pattern of EV along the signaling hierarchy. A) A visual depiction of the signaling hierarchy as defined in text and Methods. B) Network plots of the signaling hierarchy. Each layer corresponds to the corresponding layer in A. Node colors show EVexpo values of corresponding genes and lines indicate directed protein-protein interactions. C) Heatmap of enrichment p-values of each gene class as defined in Kim et al (2005) for genes in corresponding signaling hierarchy levels. Colors indicate negative log (base 10) of p-values as determined by hypergeometric distribution formula. D) Boxplots of EV values of RS level genes with class I, II and III promoters. P-values of difference were calculated by Wilcoxon rank sum test.
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Related In: Results  -  Collection

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Figure 3: Pattern of EV along the signaling hierarchy. A) A visual depiction of the signaling hierarchy as defined in text and Methods. B) Network plots of the signaling hierarchy. Each layer corresponds to the corresponding layer in A. Node colors show EVexpo values of corresponding genes and lines indicate directed protein-protein interactions. C) Heatmap of enrichment p-values of each gene class as defined in Kim et al (2005) for genes in corresponding signaling hierarchy levels. Colors indicate negative log (base 10) of p-values as determined by hypergeometric distribution formula. D) Boxplots of EV values of RS level genes with class I, II and III promoters. P-values of difference were calculated by Wilcoxon rank sum test.
Mentions: Based on the observations above, we reasoned that extracellular ligands for cellular transmembrane receptors may be more variable than their receptors, meaning that cells are more likely to modulate the expression levels of secreted factors rather than their receptors in response to extracellular cues. We compared EVs of genes annotated as "receptor binding" (GO:0005102), "growth factor activity" (GO:0008083) or "cytokine activity" (GO:0005125) and "extracellular space" (GO:0005615) (SF list, n = 269 genes) to those annotated as "transmembrane receptor activity" (GO:0004888), "receptor activity" (GO:0004872) and "plasma membrane" (GO:0005886) (GR list, n = 1038 genes) (see Additional file 11). Although EVs of both classes are significantly higher when compared to the rest of genes, EVs of the SF list are significantly higher than those of the GR list (see Figure 3B). We wanted to determine if EVs of genes involved in signal transduction reflect the hierarchical position of the corresponding signaling molecules within the signaling network. In order to answer this question, we compiled a comperehensive signaling network from online databases (5499 genes and ~22,000 interactions, see Methods), and defined 5 levels of signaling hierarchy based on the positions of the signaling molecules (Figure 3A). The first level, growth factor modulators (GM class), are secreted molecules that modulate the activities of receptor-binding secreted factors. This class includes genes such as SFRP2 (Secreted Frizzled-Related Protein 2, regulator of WNT proteins), MMP1 (matrix metaloprotease 1, regulator of various growth factors/cytokines), IGFBP1 (IGF binding protein 1) and LTBP1 (latent TGF-beta binding protein). The next two levels are secreted factors (SF) and receptors (GR), explained above. Receptor substrates (RS) are molecules immediately downstream of receptors (GR), such as G-proteins (GNA genes), receptor-associated kinases (e.g. IRAK genes, ADRBK2, JAK1), and adaptor proteins (e.g. GRB2, SOS1-2, FADD, IRS1) among others; and the next class are molecules that mediate signal transduction downstream of RS (RS2) (see Methods). Strikingly, EV patterns of these levels display a gradient, with the GM level being the most variable, and RS being the least variable among these hierarchy levels (Figure 3B). This pattern is also reproduced with EVCK values (Additional file 10). This suggests that transcriptional regulation of intracellular signaling pathways mostly happens at the level of secreted growth factor modulators and growth factors, while signaling molecules immediately downstream of signaling receptors seem to be the least transcriptionally modulated. Accordingly, the RS and RS2 levels are mostly found in class I through III of genes based on their PIC occupancy, while GM, SF and GR levels are in class IV (Figure 3C).

Bottom Line: Our analysis shows that this pattern of EV reflects functional centrality: proteins with highly specific signaling functions are modulated more frequently than those with highly central functions in the network, which is also consistent with previous studies on tissue-specific gene expression.Interestingly, these patterns of EV along the signaling network hierarchy have significant correlations with promoter architectures of respective genes.Our analyses suggest a generic systems level mechanism of regulation of the cellular signaling network at the transcriptional level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 7435 Fannin St, Houston, TX 77054, USA. kkomurov@mdanderson.org

ABSTRACT

Background: Understanding organizational principles of cellular networks is one of the central goals of systems biology. Although much has been learnt about gene expression programs under specific conditions, global patterns of expressional variation (EV) of genes and their relationship to cellular functions and physiological responses is poorly understood.

Results: To understand global principles of relationship between transcriptional regulation of human genes and their functions, we have leveraged large-scale datasets of human gene expression measurements across a wide spectrum of cell conditions. We report that human genes are highly diverse in terms of their EV; while some genes have highly variable expression pattern, some seem to be relatively ubiquitously expressed across a wide range of conditions. The wide spectrum of gene EV strongly correlates with the positioning of proteins within the signaling network hierarchy, such that, secreted extracellular receptor ligands and membrane receptors have the highest EV, and intracellular signaling proteins have the lowest EV in the genome. Our analysis shows that this pattern of EV reflects functional centrality: proteins with highly specific signaling functions are modulated more frequently than those with highly central functions in the network, which is also consistent with previous studies on tissue-specific gene expression. Interestingly, these patterns of EV along the signaling network hierarchy have significant correlations with promoter architectures of respective genes.

Conclusion: Our analyses suggest a generic systems level mechanism of regulation of the cellular signaling network at the transcriptional level.

Show MeSH