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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.

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Network of interactions of RS and RS2 level genes with high (>0.9) and low(<0.1) EV. Colors of nodes indicate EV according to the color key.
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Figure 5: Network of interactions of RS and RS2 level genes with high (>0.9) and low(<0.1) EV. Colors of nodes indicate EV according to the color key.

Mentions: Next, we asked whether the correlation of EV patterns of signaling genes with their positioning within the signaling hierarchy has a biological significance in terms of regulation of signaling pathways. Secreted factors are very specific in terms of their signaling targets (e.g. the chemokine CXCL12 specifically activates the G-protein coupled receptor CXCR4) therefore variation of their levels through transcriptional regulation may provide a high level of specificity in the regulation of signaling pathways. However, the receptor substrates are utilized by many signaling pathways (e.g. G-proteins are utilized by a large variety of G-protein coupled receptors), and therefore variation in their expression can lead to major rearrangements in the signaling architecture of the cell. Therefore, it is possible that transcriptional regulation of signaling in response to extracellular cues involves highly selective activation/inhibition of specific pathways, rather than involving large rearrangements of the signaling network. In order to test this, we compared total number of protein-protein interactions within each hierarchical class. Since the functions of signaling molecules mainly involve protein-protein interactions, the total number of protein-protein interactions of a signaling protein may provide an estimate of the number of different processes/functions that it can be involved in. Indeed, the RS class has the most overall number of interactions among all the classes (Figure 4A). In order to see if lower EV of most central proteins is a general trend in the intracellular protein interaction network, we correlated total number of interactions of the RS and RS2 proteins with their EVs. There is a significant negative correlation of EVs of RS and RS2 proteins and their number of protein interactions (Figure 4B, Spearman's ρ = -0.27, n = 1189, P < 10-20), which supports our hypothesis that differential expressional variation of genes within the signaling hierarchy can at least in part be explained by their functional centrality in the signaling network. Moreover, the RS and RS2 level proteins with high EV (EV > 0.9) have significantly less number of protein-protein interactions than those with low EV (EV < 0.1) (Figure 4C). In addition, the intracellular signaling genes with Class II promoters, which are mainly condition-specific (see Figure 3D), have significantly less number of protein-protein interactions than those with Class I promoters (Figure 4D), which are mainly constitutive (see Figure 3D). In order to get a view of the layout of proteins with different EVs within the signaling network, we plotted the signaling network of proteins of the RS and RS2 levels with high and low EVs. This network in Figure 5 shows a clear differential distribution of high and low EV proteins. While proteins with low EV are mainly located in the central dense regions of the network, those with high EV are mainly located at the periphery and generally have sparser connections. These observations support our hypothesis that condition-specific genes encode proteins with less central roles in the signaling network. The finding that genes with lowest EVs mostly comprise genes involved in the cellular homeostatic processes (transcription, translation, etc...), which can be regarded as the most central cellular processes, also adds to the hypothesis that mRNA levels of genes with highest functional centrality in the cell are modulated less and the most variable genes are those encoding more specialized regulatory proteins.


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

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

Network of interactions of RS and RS2 level genes with high (>0.9) and low(<0.1) EV. Colors of nodes indicate EV according to the color key.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992512&req=5

Figure 5: Network of interactions of RS and RS2 level genes with high (>0.9) and low(<0.1) EV. Colors of nodes indicate EV according to the color key.
Mentions: Next, we asked whether the correlation of EV patterns of signaling genes with their positioning within the signaling hierarchy has a biological significance in terms of regulation of signaling pathways. Secreted factors are very specific in terms of their signaling targets (e.g. the chemokine CXCL12 specifically activates the G-protein coupled receptor CXCR4) therefore variation of their levels through transcriptional regulation may provide a high level of specificity in the regulation of signaling pathways. However, the receptor substrates are utilized by many signaling pathways (e.g. G-proteins are utilized by a large variety of G-protein coupled receptors), and therefore variation in their expression can lead to major rearrangements in the signaling architecture of the cell. Therefore, it is possible that transcriptional regulation of signaling in response to extracellular cues involves highly selective activation/inhibition of specific pathways, rather than involving large rearrangements of the signaling network. In order to test this, we compared total number of protein-protein interactions within each hierarchical class. Since the functions of signaling molecules mainly involve protein-protein interactions, the total number of protein-protein interactions of a signaling protein may provide an estimate of the number of different processes/functions that it can be involved in. Indeed, the RS class has the most overall number of interactions among all the classes (Figure 4A). In order to see if lower EV of most central proteins is a general trend in the intracellular protein interaction network, we correlated total number of interactions of the RS and RS2 proteins with their EVs. There is a significant negative correlation of EVs of RS and RS2 proteins and their number of protein interactions (Figure 4B, Spearman's ρ = -0.27, n = 1189, P < 10-20), which supports our hypothesis that differential expressional variation of genes within the signaling hierarchy can at least in part be explained by their functional centrality in the signaling network. Moreover, the RS and RS2 level proteins with high EV (EV > 0.9) have significantly less number of protein-protein interactions than those with low EV (EV < 0.1) (Figure 4C). In addition, the intracellular signaling genes with Class II promoters, which are mainly condition-specific (see Figure 3D), have significantly less number of protein-protein interactions than those with Class I promoters (Figure 4D), which are mainly constitutive (see Figure 3D). In order to get a view of the layout of proteins with different EVs within the signaling network, we plotted the signaling network of proteins of the RS and RS2 levels with high and low EVs. This network in Figure 5 shows a clear differential distribution of high and low EV proteins. While proteins with low EV are mainly located in the central dense regions of the network, those with high EV are mainly located at the periphery and generally have sparser connections. These observations support our hypothesis that condition-specific genes encode proteins with less central roles in the signaling network. The finding that genes with lowest EVs mostly comprise genes involved in the cellular homeostatic processes (transcription, translation, etc...), which can be regarded as the most central cellular processes, also adds to the hypothesis that mRNA levels of genes with highest functional centrality in the cell are modulated less and the most variable genes are those encoding more specialized regulatory proteins.

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