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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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Large scatter in collective mode and linear distribution in acute-stochastic mode.Genome-wide single ORFs (left panels) expression changes (Δx) for 0–1 h between genotypes: wildtype vs. A) MyD88 KO, B) TRIF KO, C) DKO; TRIF KO vs. D) MyD88 KO and E) DKO; F) MyD88 KO vs. DKO. Right panels: corresponding plots for group of 200 ORFs, sorted by their expression change in the corresponding genotype (x-axis). + and − indicate average of expression change of the upregulated and downregulated ORFs in each group, respectively. Arrows indicate groups containing the acute-stochastic mode.
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pone-0004905-g006: Large scatter in collective mode and linear distribution in acute-stochastic mode.Genome-wide single ORFs (left panels) expression changes (Δx) for 0–1 h between genotypes: wildtype vs. A) MyD88 KO, B) TRIF KO, C) DKO; TRIF KO vs. D) MyD88 KO and E) DKO; F) MyD88 KO vs. DKO. Right panels: corresponding plots for group of 200 ORFs, sorted by their expression change in the corresponding genotype (x-axis). + and − indicate average of expression change of the upregulated and downregulated ORFs in each group, respectively. Arrows indicate groups containing the acute-stochastic mode.

Mentions: We observed earlier from auto and cross-correlations that the gene expression responses between genotypes are distinct from one another. To understand this in depths, we compared genome-wide expression changes between genotypes for 0–1 h, total of 6 combinations (Wildtype vs. MyD88 KO, Wildtype vs. TRIF KO, Wildtype vs. DKO, TRIF KO vs. MyD88 KO, TRIF KO vs. DKO and MyD88 KO vs. DKO) (Figure 6A–F). We plotted the expression change (Δx) of single ORF as well as taking the average value of each group of ORFs sorted from highest to lowest expressions. We observed i) large scatter in expression distributions around the origin for ORFs in the collective mode and ii) linear expression distribution of ORFs in the acute-stochastic mode (Figure 6A–F, left panels). These results further confirm biphasic response of LPS stimulation.


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)

Large scatter in collective mode and linear distribution in acute-stochastic mode.Genome-wide single ORFs (left panels) expression changes (Δx) for 0–1 h between genotypes: wildtype vs. A) MyD88 KO, B) TRIF KO, C) DKO; TRIF KO vs. D) MyD88 KO and E) DKO; F) MyD88 KO vs. DKO. Right panels: corresponding plots for group of 200 ORFs, sorted by their expression change in the corresponding genotype (x-axis). + and − indicate average of expression change of the upregulated and downregulated ORFs in each group, respectively. Arrows indicate groups containing the acute-stochastic mode.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654147&req=5

pone-0004905-g006: Large scatter in collective mode and linear distribution in acute-stochastic mode.Genome-wide single ORFs (left panels) expression changes (Δx) for 0–1 h between genotypes: wildtype vs. A) MyD88 KO, B) TRIF KO, C) DKO; TRIF KO vs. D) MyD88 KO and E) DKO; F) MyD88 KO vs. DKO. Right panels: corresponding plots for group of 200 ORFs, sorted by their expression change in the corresponding genotype (x-axis). + and − indicate average of expression change of the upregulated and downregulated ORFs in each group, respectively. Arrows indicate groups containing the acute-stochastic mode.
Mentions: We observed earlier from auto and cross-correlations that the gene expression responses between genotypes are distinct from one another. To understand this in depths, we compared genome-wide expression changes between genotypes for 0–1 h, total of 6 combinations (Wildtype vs. MyD88 KO, Wildtype vs. TRIF KO, Wildtype vs. DKO, TRIF KO vs. MyD88 KO, TRIF KO vs. DKO and MyD88 KO vs. DKO) (Figure 6A–F). We plotted the expression change (Δx) of single ORF as well as taking the average value of each group of ORFs sorted from highest to lowest expressions. We observed i) large scatter in expression distributions around the origin for ORFs in the collective mode and ii) linear expression distribution of ORFs in the acute-stochastic mode (Figure 6A–F, left panels). These results further confirm biphasic response of LPS stimulation.

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