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Abstract
Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity.
Highlights
Cells must make decisions in noisy environments and have to decrease the chance of an errant response
Dynamics of NF-κB activation depend on input temporal profile, so that a long duration, low-dose (LL) signal induces delayed, heterogeneous activation timing in the population while a short duration, strong amplitude (SS) signal with the same area causes rapid activation without cell-to-cell timing variability (Figure 1). These results reveal a function for digital signaling beyond simple noise filtering: digital activation controls fate along a two dimensional space by allowing an input signal to independently control the population response and single-cell response though modulation of signal area and shape
Under low intensity LPS stimulation, most cells did not respond (Figure 2C,D). This was a similar effect as previously observed under Tumor Necrosis Factor (TNF) (Tay et al, 2010; Turner et al, 2010). While both LPS and TNF are digital in preserving first peak area, the TNF-induced NF-κB initial peak becomes flatter and wider with increasing response time but unchanging onset time for Digital, time-delayed NF-κB activation under varied LPS dose stimulation. (A) Cells process pathogen signal dose and duration to dynamically activate NF-κB, which induces gene expression and coordinates the innate immune response
Summary
Cells must make decisions in noisy environments and have to decrease the chance of an errant response. One way cells can reduce sensitivity to noise is through digital or switch-like activation, such that only sufficiently strong signal exceeds an internal threshold and initiates a response. It was found that inflammasome signaling leads to all-or-none caspase activation that mediates apoptosis (Liu et al, 2013). Both amplitude (dose) and duration of input signals provide information that regulates cellular decisions. Glucose sensing in plants showed that cells have gene regulatory network mechanisms to allow similar responses to a short, intense or sustained, moderate stimulus (Fu et al, 2014).
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