Modeling aging and its impact on cellular function and organismal behavior

In Bacillus subtilis, a master regulator Spo0A controls several cell-differentiation pathways. Under moderate starvation, phosphorylated Spo0A (Spo0A~P) induces biofilm formation by indirectly activating genes controlling matrix production in a subpopulation of cells via a SinI-SinR-SlrR network. Under severe starvation, Spo0A~P induces sporulation by directly and indirectly regulating sporulation gene expression. However, what determines the heterogeneity of individual cell fates is not fully understood. In particular, it is still unclear why, despite being controlled by a single master regulator, biofilm matrix production and sporulation are mutually exclusive on a single-cell level. In this work, with mathematical modeling, we showed that the fluctuations in the growth rate and the intrinsic noise amplified by the bistability in the SinI-SinR-SlrR network could explain the single-cell distribution of matrix production. Moreover, we predicted an incoherent feed-forward loop: the decrease in the cellular growth rate activates matrix production by increasing in Spo0A phosphorylation level but represses it via changing the relative concentrations of SinR and SlrR. Experimental data provide evidence to support model predictions. In particular, we demonstrate how the degree to which matrix production and sporulation appear mutually exclusive is affected by genetic perturbations.

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“…By acquiring detailed knowledge about biophysical properties of individual aggregates from single-molecule super-resolution microscopy data, we could gain insights in protein aggregation as a cellular response to exposure to oxidative and salt stress. While the analysis of this type of data alone reveals novel insights in aggregation formation and regulation, it also opens up new possibilities to build or complement mathematical models of protein aggregation with interesting applications in ageing and age-related diseases [54]. A major driver of ageing is the asymmetric distribution of damaged components between progeny and progenitor cells (retention) [55].…”

Section: Discussionmentioning

confidence: 99%

The effect of stress on biophysical characteristics of misfolded protein aggregates in living Saccharomyces cerevisiae cells

Schnitzer

Welkenhuysen

Leake

et al. 2022

Experimental Gerontology

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Modeling aging and its impact on cellular function and organismal behavior

Cited by 9 publications

References 106 publications

The Slowdown of Growth Rate Controls the Single-Cell Distribution of Biofilm Matrix Production via an SinI-SinR-SlrR Network

The Slowdown of Growth Rate Controls the Single-Cell Distribution of Biofilm Matrix Production via an SinI-SinR-SlrR Network

The slowdown of growth rate controls the single-cell distribution of biofilm matrix production via a SinI-SinR-SlrR network

The effect of stress on biophysical characteristics of misfolded protein aggregates in living Saccharomyces cerevisiae cells

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