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Emergent genome-wide control in wildtype and genetically mutated lipopolysaccarides-stimulated macrophages.

Tsuchiya M, Piras V, Choi S, Akira S, Tomita M, Giuliani A, Selvarajoo K - PLoS ONE (2009)

Bottom Line: Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response.With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries.Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

View Article: PubMed Central - PubMed

Affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. tsuchiya@ttck.keio.ac.jp

ABSTRACT
Large-scale gene expression studies have mainly focused on highly expressed and 'discriminatory' genes to decipher key regulatory processes. Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response. Here we comprehensively analyzed the temporal oligonucleotide microarray data of lipopolysaccharide (LPS) stimulated macrophages in 4 genotypes; wildtype, Myeloid Differentiation factor 88 (MyD88) knockout (KO), TIR-domain-containing adapter-inducing interferon-beta (TRIF) KO and MyD88/TRIF double KO (DKO). Pearson correlations computed on the whole genome expression between different genotypes are extremely high (>0.98), indicating a strong co-regulation of the entire expression network. Further correlation analyses reveal genome-wide response is biphasic, i) acute-stochastic mode consisting of small number of sharply induced immune-related genes and ii) collective mode consisting of majority of weakly induced genes of diverse cellular processes which collectively adjust their expression level. Notably, temporal correlations of a small number of randomly selected genes from collective mode show scalability. Furthermore, in collective mode, the transition from large scatter in expression distributions for single ORFs to smooth linear lines emerges as an organizing principle when grouping of 50 ORFs and above. With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries. Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

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LPS induces biphasic acute-stochastic and collective modes of response in wildtype and single KOs but not DKO.A) Auto-correlation profiles of all genotypes when removing one by one up to 300 ORFs highest upregulated ORFs from 0 to 1 hr (in terms of expression change: Δx = x(1 h)−x(0 h)). B) Plot of average auto-correlations slopes of 0–1 h in A). Since DKO possesses only collective mode, we used average slope of DKO curve at N = 10 to distinguish biphasic transition (dotted gray line). Wildtype and single KO cross this slope at about N = 80 and N = 50 ORFs, respectively. This biphasic transition point further suggests collective mode. No biphasic behavior was found for C) randomly selected or D) downregulated ORFs. Confirmation of collective mode: E) Standard deviation (SD) of auto-correlation (0–1 h) of groups of randomly chosen ORFs in steps of 10 up to 300 from whole genome. Each point represents average SD of 30 groups, error bars represent highest and lowest SD. F) As in E) for 1–4 h auto-correlation. G) Auto-correlations of 80 highly expressed ORFs representing acute-stochastic mode in the wildtype. H) Average auto-correlations of 30 extractions of 80 randomly chosen ORFs in the wildtype collective mode.
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pone-0004905-g004: LPS induces biphasic acute-stochastic and collective modes of response in wildtype and single KOs but not DKO.A) Auto-correlation profiles of all genotypes when removing one by one up to 300 ORFs highest upregulated ORFs from 0 to 1 hr (in terms of expression change: Δx = x(1 h)−x(0 h)). B) Plot of average auto-correlations slopes of 0–1 h in A). Since DKO possesses only collective mode, we used average slope of DKO curve at N = 10 to distinguish biphasic transition (dotted gray line). Wildtype and single KO cross this slope at about N = 80 and N = 50 ORFs, respectively. This biphasic transition point further suggests collective mode. No biphasic behavior was found for C) randomly selected or D) downregulated ORFs. Confirmation of collective mode: E) Standard deviation (SD) of auto-correlation (0–1 h) of groups of randomly chosen ORFs in steps of 10 up to 300 from whole genome. Each point represents average SD of 30 groups, error bars represent highest and lowest SD. F) As in E) for 1–4 h auto-correlation. G) Auto-correlations of 80 highly expressed ORFs representing acute-stochastic mode in the wildtype. H) Average auto-correlations of 30 extractions of 80 randomly chosen ORFs in the wildtype collective mode.

Mentions: We analyzed the change (i.e., difference of expression) of response based on Pearson r of all genotypes by removing highest up- and down-regulated ORFs (one by one up to 300 ORFs) between 0 to 1 hr. For removing highest up-regulated ORFs, a biphasic (hyperbolic) phenomenon emerges in wildtype and single KOs but not in DKO (Figure 4A). The gradient of curves is steep up to the removal of about 80 ORFs in wildtype and 50 ORFs in both single KOs after which the slope gentles. In contrast, in DKO, only the gentle gradient exists (Figure 4B). As control, we next compared randomly removed ORFs in similar steps and found Pearson r (0–1 h) of all genotypes does not change noticeably (Figure 4C). This result points to a transition in the response: a small fraction of ‘acute’ responding ORFs, and the majority of ORFs responding ‘weakly’. Notably, for downregulated ORFs, biphasic response is not observed for any genotype (Figure 4D).


Emergent genome-wide control in wildtype and genetically mutated lipopolysaccarides-stimulated macrophages.

Tsuchiya M, Piras V, Choi S, Akira S, Tomita M, Giuliani A, Selvarajoo K - PLoS ONE (2009)

LPS induces biphasic acute-stochastic and collective modes of response in wildtype and single KOs but not DKO.A) Auto-correlation profiles of all genotypes when removing one by one up to 300 ORFs highest upregulated ORFs from 0 to 1 hr (in terms of expression change: Δx = x(1 h)−x(0 h)). B) Plot of average auto-correlations slopes of 0–1 h in A). Since DKO possesses only collective mode, we used average slope of DKO curve at N = 10 to distinguish biphasic transition (dotted gray line). Wildtype and single KO cross this slope at about N = 80 and N = 50 ORFs, respectively. This biphasic transition point further suggests collective mode. No biphasic behavior was found for C) randomly selected or D) downregulated ORFs. Confirmation of collective mode: E) Standard deviation (SD) of auto-correlation (0–1 h) of groups of randomly chosen ORFs in steps of 10 up to 300 from whole genome. Each point represents average SD of 30 groups, error bars represent highest and lowest SD. F) As in E) for 1–4 h auto-correlation. G) Auto-correlations of 80 highly expressed ORFs representing acute-stochastic mode in the wildtype. H) Average auto-correlations of 30 extractions of 80 randomly chosen ORFs in the wildtype collective mode.
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Related In: Results  -  Collection

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pone-0004905-g004: LPS induces biphasic acute-stochastic and collective modes of response in wildtype and single KOs but not DKO.A) Auto-correlation profiles of all genotypes when removing one by one up to 300 ORFs highest upregulated ORFs from 0 to 1 hr (in terms of expression change: Δx = x(1 h)−x(0 h)). B) Plot of average auto-correlations slopes of 0–1 h in A). Since DKO possesses only collective mode, we used average slope of DKO curve at N = 10 to distinguish biphasic transition (dotted gray line). Wildtype and single KO cross this slope at about N = 80 and N = 50 ORFs, respectively. This biphasic transition point further suggests collective mode. No biphasic behavior was found for C) randomly selected or D) downregulated ORFs. Confirmation of collective mode: E) Standard deviation (SD) of auto-correlation (0–1 h) of groups of randomly chosen ORFs in steps of 10 up to 300 from whole genome. Each point represents average SD of 30 groups, error bars represent highest and lowest SD. F) As in E) for 1–4 h auto-correlation. G) Auto-correlations of 80 highly expressed ORFs representing acute-stochastic mode in the wildtype. H) Average auto-correlations of 30 extractions of 80 randomly chosen ORFs in the wildtype collective mode.
Mentions: We analyzed the change (i.e., difference of expression) of response based on Pearson r of all genotypes by removing highest up- and down-regulated ORFs (one by one up to 300 ORFs) between 0 to 1 hr. For removing highest up-regulated ORFs, a biphasic (hyperbolic) phenomenon emerges in wildtype and single KOs but not in DKO (Figure 4A). The gradient of curves is steep up to the removal of about 80 ORFs in wildtype and 50 ORFs in both single KOs after which the slope gentles. In contrast, in DKO, only the gentle gradient exists (Figure 4B). As control, we next compared randomly removed ORFs in similar steps and found Pearson r (0–1 h) of all genotypes does not change noticeably (Figure 4C). This result points to a transition in the response: a small fraction of ‘acute’ responding ORFs, and the majority of ORFs responding ‘weakly’. Notably, for downregulated ORFs, biphasic response is not observed for any genotype (Figure 4D).

Bottom Line: Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response.With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries.Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

View Article: PubMed Central - PubMed

Affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. tsuchiya@ttck.keio.ac.jp

ABSTRACT
Large-scale gene expression studies have mainly focused on highly expressed and 'discriminatory' genes to decipher key regulatory processes. Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response. Here we comprehensively analyzed the temporal oligonucleotide microarray data of lipopolysaccharide (LPS) stimulated macrophages in 4 genotypes; wildtype, Myeloid Differentiation factor 88 (MyD88) knockout (KO), TIR-domain-containing adapter-inducing interferon-beta (TRIF) KO and MyD88/TRIF double KO (DKO). Pearson correlations computed on the whole genome expression between different genotypes are extremely high (>0.98), indicating a strong co-regulation of the entire expression network. Further correlation analyses reveal genome-wide response is biphasic, i) acute-stochastic mode consisting of small number of sharply induced immune-related genes and ii) collective mode consisting of majority of weakly induced genes of diverse cellular processes which collectively adjust their expression level. Notably, temporal correlations of a small number of randomly selected genes from collective mode show scalability. Furthermore, in collective mode, the transition from large scatter in expression distributions for single ORFs to smooth linear lines emerges as an organizing principle when grouping of 50 ORFs and above. With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries. Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

Show MeSH
Related in: MedlinePlus