Macrophage Genome-Wide Control Figure 8. Deciphering gene regulatory mechanisms from the emergent signature. Linear regressions of genome-wide expression changes (Dx) between genotypes after the removal of global shifts in Figure 7: A) wildtype vs. MyD88 KO, B) wildtype vs. TRIF KO, C) wildtype vs. DKO, for group of 1000 ORFs, sorted from highest to lowest expressions change in wildtype. Each point represents the average expression changes of 1000 ORFs (see Methods). Distributions are approximated to linear equations represented by y = ax+b (main text) so as to obtain best fit. Flat distributions are fitted to the average of their points (R2 = 0). D) Gene clustering. The 3798 ORFs upregulated in TRIF KO and downregulated in MyD88 KO for WTc+ (top panel) and the 1916 ORFs downregulated in TRIF KO and DKO, and upregulated in MyD88 KO for WTc2 (bottom panel) were selected to determine biological processes regulated in whole genome (see maintext). E) Individual effects of M, T, MT and U on the biological processes regulated in collective mode of WTc+and WTc2. Arrows indicate activation through dominant transcription and T-shaped lines indicate repression through dominant mRNA decay. doi:10.1371/journal.pone.0004905.g008 grouped. Other manifestations of such collective behavior, arising from the functional relations between gene expressions, were observed in terms of coordinated genome-wide expression waves [30,31]. The transition from scatter to linearity was observed in the distribution of whole genome expression when grouping of 50 ORFs and above. Notably similar transition occurs for the distribution of single gene expression of cells in culture when the intrinsic (uncorrelated) noise becomes low [32]. Thus, our work also reveals the regulation by correlations in gene expression fluctuations [33]. However, it is important to stress that our data refers to large ensembles of cells, unlike single cell measurements, and thus exact discrimination between intrinsic and extrinsic noise PLoS ONE | www.plosone.org 10 March 2009 | Volume 4 | Issue 3 | e4905