Biology subjects

Welkenhuysen, N.

Publications and source records attributed to Welkenhuysen, N..

4 recordsLinked to original sources

bioRxiv2021

PEPSDI: Scalable and flexible inference framework for stochastic dynamic single-cell models

Mathematical modelling is an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. This requires statistical methods to infer unknown model parameters from dynamic, multi-individual data accounting for heterogeneity caused by both intrinsic and extrinsic noise. Here we present PEPSDI, a scalable and flexible framework for Bayesian inference in state-space mixed-effects stochastic dynamic single-cell models. Unlike previous frameworks, PEPSDI imposes a few modelling assumptions when inferring unknown model parameters from time-lapse data. Specifically, it can infer model parameters when intrinsic noise is modelled by either exact or approximate stochastic simulators, and when extrinsic noise is modelled by either time-varying, or time-constant parameters that vary between cells. This allowed us to identify hexokinase activity as a source of extrinsic noise, and to deduce that sugar availability dictates cell-to-cell variability in the budding yeast Saccharomyces cerevisiae SNF1 nutrient sensing pathway.

systems biology↗

bioRxiv2021

Localization and phosphorylation in the Snf1 network is controlled by two independent pathways

AMPK/SNF1 is the master regulator of energy homeostasis in eukaryotic cells and has a key role in glucose de-repression. If glucose becomes depleted, Snf1 is phosphorylated and activated. Activation of Snf1 is required but is not sufficient for mediating glucose de-repression indicating a second glucose-regulated step that adjusts the Snf1 pathway. To elucidate this regulation, we further explore the spatial dynamics of Snf1 and Mig1 and how they are controlled by concentrations of hexose sugars. We utilize fluorescence recovery after photobleaching (FRAP) to study the movement of Snf1 and how it responds to external glucose concentrations. We show that the Snf1 pathway reacts to the presence of glucose. Furthermore, we identify a negative feedback loop regulating Snf1 activity. Our data offer insight into the true complexity of regulation of this central signaling pathway by one signal (glucose depletion) interpreted by the cell in different ways.

cell biology↗

bioRxiv2019

Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modification of PKA

Peroxiredoxins are H2O2 scavenging enzymes that also carry H2O2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H2O2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H2O2, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by H2O2 and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modification of the conserved Cys243 inhibits the phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity, and preventing Thr241 phosphorylation can overcome the H2O2 sensitivity of Tsa1-deficient cells. Results support a model of aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits, including a peroxiredoxin-dependent response to H2O2.

biochemistry↗

bioRxiv2018

The triangle of ageing: a model of how repair, resilience to damage and asymmetric segregation are responses to replicative ageing

Accumulation of damaged proteins is a hallmark of ageing, occurring in organisms ranging from bacteria and yeast to mammalian cells. During cell division in Saccharomyces cerevisiae, damaged proteins are retained within the mother cell, resulting in a new daughter cell with full replicative potential and an ageing mother with a reduced replicative lifespan (RLS). The cell-specific features determining the lifespan remain elusive. It has been suggested that the RLS is dependent on the ability of the cell to repair and retain pre-existing damage. To deepen the understanding of how these factors influence the life span of individual cells, we developed and experimentally validated a dynamic model of damage accumulation accounting for replicative ageing. The model includes five essential properties: cell growth, damage formation, damage repair, cell division and cell death, represented in a theoretical framework describing the conditions allowing for replicative ageing, starvation, immortality or clonal senescence. We introduce the resilience to damage, which can be interpreted as the difference in volume between an old and a young cell. We show that the capacity to retain damage deteriorates with high age, that asymmetric division allows for retention of damage, and that there is a trade-off between retention and the resilience property. Finally, we derive the maximal degree of asymmetry as a function of resilience, proposing that asymmetric cell division is beneficial with respect to replicative ageing as it increases the RLS of a given organism. The proposed model contributes to a deeper understanding of the ageing process in eukaryotic organisms.

systems biology↗