Temporal precision of molecular events with regulation and feedback

Abstract

Cellular behaviors such as migration, division, and differentiation rely on precise timing, and yet the molecular events that govern these behaviors are highly stochastic. We investigate regulatory strategies that decrease the timing noise of molecular events. Autoregulatory feedback increases noise. Yet, we find that in the presence of regulation by a second species, autoregulatory feedback decreases noise. To explain this finding, we develop a method to calculate the optimal regulation function that minimizes the timing noise. The method reveals that the combination of feedback and regulation minimizes noise by maximizing the number of molecular events that must happen in sequence before a threshold is crossed. We compute the optimal timing precision for all two-node networks with regulation and feedback, derive a generic lower bound on timing noise, and discuss our results in the context of neuroblast migration during Caenorhabditis elegans development.

Signal processing capacity of the cellular sensory machinery regulates the accuracy of chemotaxis under complex cues

“…In cellular signal processing, intracellular protein diffusion and activation are critical to understanding the cellular sensory function (Soh et al, 2010). Not only the spatial variation but also the temporal relations were used to develop a better understanding and physically predictable models (Gupta et al, 2020).…”

Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor

“…Mathematical modeling of the regulator-based timekeeping mechanism has shown that temporal precision is enhanced when the regulated timekeeper molecule amplifies its own expression through positive feedback (Gupta et al, 2020), but the in vivo relevance of this predicted strategy is not known. mig-1 encodes a Frizzled-type Wnt receptor that triggers a BAR-1/μ-catenin-dependent signaling pathway which induces the expression of target genes that inhibit the migration of QR.pa (Mentink et al, 2014; Rella et al, 2021).…”

Regulatory strategies to schedule threshold crossing of protein levels at a prescribed time

“…Assuming different empirical forms for the regulation of gene-expression (e.g., feedback auto-regulation, activation/repression by an upstream component, etc. ), these works search for the best model parameters that minimize the noise in timing [34]- [36], [38], [39], [42], [43]. In the limiting case where protein does not degrade (or dilute), any form of feedback gives 1 Department of Electrical and Computer Engineering, University of Delaware, Newark, DE, USA {cnieto, absingh}@udel.edu 2 Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA khem@udel.edu higher noise in event timing around a fixed mean time [35].…”

“…Assuming different empirical forms for the regulation of gene-expression (e.g., feedback auto-regulation, activation/repression by an upstream component, etc. ), these works search for the best model parameters that minimize the noise in timing [34]– [36], [38], [39], [42], [43]. In the limiting case where protein does not degrade (or dilute), any form of feedback gives higher noise in event timing around a fixed mean time [35].…”