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

• Published in: iScience Vol. 26; no. 12; p. 108573
• Main Authors: Kizilirmak, Cise, Monteleone, Emanuele, García-Manteiga, José Manuel, Brambilla, Francesca, Agresti, Alessandra, Bianchi, Marco E., Zambrano, Samuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2023; Elsevier
• Subjects: Immunology; Systems biology; Transcriptomics; Systems biology; Transcriptomics; Immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108573

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 κB (NF-κB). We found that clonal populations of immortalized fibroblasts derived from a single mouse embryo display robustly distinct NF-κB dynamics upon tumor necrosis factor ɑ (TNF-ɑ) 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-κB dynamic response of the clones to TNF-ɑ and IL-1β. 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. [Display omitted] •Clones from fibroblasts of a single mouse embryo have distinct NF-κB dynamics•NF-κB oscillatory responses to TNF-α and IL-1β are different across clones•Clones have small transcriptional differences in key elements of NF-κB signaling•Modeling shows that transcriptional differences lead to distinct NF-κB dynamics Systems biology; Transcriptomics; Cell signaling; Biophysics