Uncovering a Macrophage Transcriptional Program by Integrating Evidence from Motif Scanning and Expression Dynamics
Figure 4
Two validated transcriptional regulatory interactions exhibiting high time-lagged correlations.
(A) Rel and Nfkb1. The solid line shows the expression of Rel (c-REL), and the dotted line shows the expression of Nfkb1 (p50/p105) in LPS-stimulated wild-type macrophages, over eight hours. The genes exhibit a high time-lagged correlation with a time delay of 60 minutes (across the eleven time-course experiments listed in Table S9, ρτ = 0.91 and P = 0.011; see Materials and Methods, Time-lagged Correlation, for an explanation of the statistical test). The NFκB heterodimers c-REL-p50 and c-REL-p65 are known to regulate expression of Nfkb1 [43]. The correlation at zero time lag is 0.81. (B) Irf7 and Stat1. The solid line shows the expression of Irf7 (IRF7) and the dotted line shows the expression of Stat1 (STAT1) in LPS-stimulated Atf3(−/−) macrophages. The genes exhibit a high time-lagged correlation with a time delay of 20 minutes (across the ten experiments, ρτ = 0.96 and P = 0.002). The transcription factor IRF7 has been shown to regulate the Stat1 gene expression in the innate immune response to viral infection [44]. The correlation at zero time lag is 0.95. (C) Time-lagged correlation coefficient and time-lagged correlation significance measure (see Equation 4) as a function of the time lag τ, for Irf7 and Stat1. The peak value of ρτ2 occurs at τ = 10, but the peak significance value (taking into account the lag-specific null distribution) occurs at τ = 20 min.