Macrophage Genome-Wide Control Figure 1. Simplified overview of LPS-induced signaling. LPS binds with TLR4 and activates transcription factors AP-1, NF-kB and IRF3 through MyD88- and TRIF- dependant pathways. This leads to the induction of proinflammatory cytokines and interferons. Figure modified from Akira et al. (2006). doi:10.1371/journal.pone.0004905.g001 TRIF cannot be considered to be acting along the same pathway, otherwise single and DKO’s cross-correlation should be equal and overlapping and iii) MyD88- and TRIF-dependent pathways are not completely independent, otherwise DKO’s distance from unity in terms of cross-correlation would be equal to a composition of MyD88 KO and TRIF KO individual values. These results imply the existence of synergized action between the MyD88- and TRIF- dependent pathways because the sum of single KO responses is different from DKO response [25,26] (see MT in ‘Deciphering gene regulatory mechanisms from the emergent signature’). In summary, even though we observed genome-wide strong invariance between genotypes, temporal correlation analyses reveal the difference between them. The temporal whole genome (global) response and immune (local-specific) response show distinct profiles [27]. Thus, we pondered whether there are organization principles that distinguish such different modes of response. To uncover, we next investigated Pearson r of all genotypes between 0–1 h by selectively removing ORFs from each genotype. This procedure will allow us to individualize the different contributors to the whole genome behavior. PLoS ONE | www.plosone.org 3 March 2009 | Volume 4 | Issue 3 | e4905