Small transcriptional differences among cell clones lead to distinct NF-κB dynamics

Transcription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at a single-cell level, even within homogeneous populations. We asked how such heterogeneity emerges for the nuclear factor kappa B (NF-kappa B). We found that clonal populations of immortalized fibroblasts derived from a single mouse embryo display robustly distinct NF-kappa B dynamics upon tumor necrosis factor alpha (TNF-alpha) stimulation including persistent, oscillatory, and weak activation, giving rise to differences in the transcription of its targets. By combining transcriptomics and simulations we show how less than two-fold differences in the expression levels of genes coding for key proteins of the signaling cascade and feedback system are predictive of the differences of the NF-kappa B dynamic response of the clones to TNF-alpha and IL-1 beta. We propose that small transcriptional differences in the regulatory circuit of a transcription factor can lead to distinct signaling dynamics in cells within homogeneous cell populations and among different cell types.