Small transcriptional differences lead to distinct NF-κB dynamics in quasi-identical cells

Author:

Kizilirmak Cise,Monteleone EmanueleORCID,García-Manteiga Jose M.,Brambilla Francesca,Agresti AlessandraORCID,Bianchi Marco E.ORCID,Zambrano SamuelORCID

Abstract

ABSTRACTTranscription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at single-cell level. The source of this dynamic variability is not completely understood. Here we focus on the nuclear factor κB (NF-κB), whose dynamics have been reported to cover a wide spectrum ranging from oscillatory to non-oscillatory. We show that clonal populations of immortalized fibroblasts derived from a single mouse embryo (that can hence be considered quasi-identical) display robustly distinct dynamics upon tumor necrosis ɑ (TNF-ɑ) stimulation. Combining transcriptomics, data-constrained mathematical modelling, and mRNA interference we show that small differences in the expression of genes belonging to the NF-κB regulatory circuit are predictive of the distinct responses to inflammatory stimuli observed among the clones. We propose that this transcriptional fine-tuning can be a general mechanism to produce cell subpopulations with distinct dynamic responses to stimuli within homogeneous cell populations.

Publisher

Cold Spring Harbor Laboratory

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