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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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Genome-wide invariance between wildtype, single and double KOs.Highly correlated gene expressions between genotypes, and between time points. A) Left panel: wildtype 0 h (x-axis) vs. wildtype 1 h (y-axis), right panel: wildtype 1 h (x-axis) vs. DKO 1 h (y-axis). Other combinations of genotype and time points also show similar correlations (data not shown). Each point in the plot represents the expression of a single ORF. B) Whole genome Pearson correlations between samples.
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pone-0004905-g002: Genome-wide invariance between wildtype, single and double KOs.Highly correlated gene expressions between genotypes, and between time points. A) Left panel: wildtype 0 h (x-axis) vs. wildtype 1 h (y-axis), right panel: wildtype 1 h (x-axis) vs. DKO 1 h (y-axis). Other combinations of genotype and time points also show similar correlations (data not shown). Each point in the plot represents the expression of a single ORF. B) Whole genome Pearson correlations between samples.

Mentions: LPS stimulates the MyD88- and TRIF-dependent pathways to activate the innate immune response (Figure 1). We evaluated the correlation structure of Affymetrix mouse expression data for wildtype, MyD88 KO, TRIF KO, DKO at 0, 1 and 4 hours (Methods and [10]). The analyses of only highly up- or down-regulated gene expressions ignoring lowly-expressed genes may not be sufficient to unravel genome-wide organizational principles [13]–[15]. To investigate the existence of such principles, we analyzed the whole genome cDNA microarray expression without any threshold cut-off. First, we performed Pearson correlation analysis on the entire genome expression vector. This ensemble property of the population of genes is a robust measure that is not biased by noise at the level of individual gene measurement [16], [17]. The whole genome correlations of the same cell-type between different genotypes are extremely high (Pearson r above 0.98, Figure 2A–B), indicating a strong common order parameter influencing the expression level of the entire genome, correspondent to the cell-type characterization [17]. High correlation between genotypes may suggest that technical noise of our microarray dataset is rather low [18], [19]. Furthermore, our results are coincident with the results obtained on erythroid cell lineages using the same metrics [20]. The presence of such invariant order spanning more than twenty-thousand elements (genes, ORFs) and around four orders of magnitude of expression levels is a signature of general order parameters organizing the entire cell regulation network. This organization is, in our opinion, a ‘fact of nature’ that, for its dimensions and invariance, asks for a deep thinking in analogy of what happened for other collective phenomena in physics (magnetism, laser coherence, super-fluid helium, hydrodynamic instabilities). Such strong invariance is imposed by the presence of a common attractor correspondent to the cell kind [16], [20], between all genotypes especially when we already know that MyD88 KO and DKO show significantly impaired proinflammatory responses [21]. Hence, to investigate specific proinflammatory and global LPS response, we compared the between genotypes Pearson similarities as computed both on the whole genome and on different extractions of gene subsets (random and immune-related).


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)

Genome-wide invariance between wildtype, single and double KOs.Highly correlated gene expressions between genotypes, and between time points. A) Left panel: wildtype 0 h (x-axis) vs. wildtype 1 h (y-axis), right panel: wildtype 1 h (x-axis) vs. DKO 1 h (y-axis). Other combinations of genotype and time points also show similar correlations (data not shown). Each point in the plot represents the expression of a single ORF. B) Whole genome Pearson correlations between samples.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654147&req=5

pone-0004905-g002: Genome-wide invariance between wildtype, single and double KOs.Highly correlated gene expressions between genotypes, and between time points. A) Left panel: wildtype 0 h (x-axis) vs. wildtype 1 h (y-axis), right panel: wildtype 1 h (x-axis) vs. DKO 1 h (y-axis). Other combinations of genotype and time points also show similar correlations (data not shown). Each point in the plot represents the expression of a single ORF. B) Whole genome Pearson correlations between samples.
Mentions: LPS stimulates the MyD88- and TRIF-dependent pathways to activate the innate immune response (Figure 1). We evaluated the correlation structure of Affymetrix mouse expression data for wildtype, MyD88 KO, TRIF KO, DKO at 0, 1 and 4 hours (Methods and [10]). The analyses of only highly up- or down-regulated gene expressions ignoring lowly-expressed genes may not be sufficient to unravel genome-wide organizational principles [13]–[15]. To investigate the existence of such principles, we analyzed the whole genome cDNA microarray expression without any threshold cut-off. First, we performed Pearson correlation analysis on the entire genome expression vector. This ensemble property of the population of genes is a robust measure that is not biased by noise at the level of individual gene measurement [16], [17]. The whole genome correlations of the same cell-type between different genotypes are extremely high (Pearson r above 0.98, Figure 2A–B), indicating a strong common order parameter influencing the expression level of the entire genome, correspondent to the cell-type characterization [17]. High correlation between genotypes may suggest that technical noise of our microarray dataset is rather low [18], [19]. Furthermore, our results are coincident with the results obtained on erythroid cell lineages using the same metrics [20]. The presence of such invariant order spanning more than twenty-thousand elements (genes, ORFs) and around four orders of magnitude of expression levels is a signature of general order parameters organizing the entire cell regulation network. This organization is, in our opinion, a ‘fact of nature’ that, for its dimensions and invariance, asks for a deep thinking in analogy of what happened for other collective phenomena in physics (magnetism, laser coherence, super-fluid helium, hydrodynamic instabilities). Such strong invariance is imposed by the presence of a common attractor correspondent to the cell kind [16], [20], between all genotypes especially when we already know that MyD88 KO and DKO show significantly impaired proinflammatory responses [21]. Hence, to investigate specific proinflammatory and global LPS response, we compared the between genotypes Pearson similarities as computed both on the whole genome and on different extractions of gene subsets (random and immune-related).

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