Biology subjects

Youk, H.

Publications and source records attributed to Youk, H..

6 recordsLinked to original sources

bioRxiv2022

Fundamental limits to progression of cellular life in frigid environments

Life on Earth, including for microbes and cold-blooded animals, often occurs in frigid environments. At frigid temperatures, nearly all intracellular processes slow down which is colloquially said to decelerate lifes pace and, potentially, aging. But even for one cell, an outstanding conceptual challenge is rigorously explaining how the slowed-down intracellular processes collectively sustain a cells life and set its pace. Here, by monitoring individual yeast cells for months at near-freezing temperatures, we show how global gene-expression dynamics and Reactive Oxygen Species (ROS) act together as the primary factors that dictate and constrain the pace at which a budding yeasts life can progresses in frigid environments. We discovered that yeast cells help each other in surviving and dividing at frigid temperatures. By investigating the underlying mechanism, involving glutathione secretion, we discovered that ROS is the primary determinant of yeasts ability to survive and divide at near-freezing temperatures. Observing days-to-months-long cell-cycle progression in individual cells revealed that ROS inhibits S-G2-M (replicative) phase while elongating G1 (growth) phase up to a temperature-dependent threshold duration, beyond which yeast cannot divide and bursts as an unsustainably large cell. We discovered that an interplay between global gene-expression speed and ROS sets the threshold G1-duration by measuring rates of genome-wide transcription and protein synthesis at frigid temperatures and then incorporating them into a mathematical model. The same interplay yields unbeatable "speed limits" for cell cycling - shortest and longest allowed doubling times - at each temperature. These results establish quantitative principles for engineering cold-tolerant microbes and reveal how frigid temperatures can fundamentally constrain microbial life and cell cycle at the systems-level.

systems biology↗

bioRxiv2020

Global community effect: large-scale cooperation yields collective survival of differentiating embryonic stem cells

Cells can help each other replicate by communicating with diffusible molecules. In cell cultures, molecules may diffuse within a cell colony or between adjacent or distant colonies. Determining which cell helps which cells replication is challenging. We developed a systematic approach, integrating modeling and experiments, for determining the length-scales of cell-cell communication (from microns to centimeters). With this approach, we discovered that differentiating murine ES cells, scattered across centimeters on a dish, communicate over millimeters to form one macroscopic entity that survives if and only if its centimeter-scale population-density is above a threshold value. Single-cell-level measurements, transcriptomics, and modeling revealed that this "macroscopic quorum sensing" arises from differentiating ES cells secreting and sensing survival-promoting FGF4 that diffuses over millimeters and activates YAP1-induced survival mechanisms. Through the same mechanism, a lone macroscopic, but not microscopic, colony survives differentiation. Our work rigorously establishes that in vitro ES-cell differentiation relies on macroscopic cooperation.

systems biology↗

bioRxiv2019

Dormancy as a spectrum measuring spore’s proximity to death and to replicative life

Dormancy is colloquially considered as extending lifespan by being still. Starved yeasts form dormant spores that wake-up (germinate) when nutrients reappear but cannot germinate (die) after some time. What sets their lifespans and how they age are open questions because what processes occur - and by how much - within each dormant spore remains unclear. With single-cell-level measurements, we discovered how dormant yeast spores age and die: spores have a quantifiable gene-expressing ability during dormancy that decreases over days to months until it vanishes, causing death. Specifically, each spore has a different probability of germinating that decreases because its ability to - without nutrients - express genes decreases, as revealed by a synthetic circuit that forces GFP expression during dormancy. Decreasing amounts of molecules required for gene expression - including RNA polymerases - decreases gene-expressing ability which then decreases chances of germinating. Spores gradually lose these molecules because they are produced too slowly compared to their degradations, causing gene-expressing ability to eventually vanish and, thus, death. Our work provides a systems-level view of dormancy-to-death transition. Short summaryThis study identifies systems-level quantities that decay during dormancy in Saccharomyces cerevisiae spores and thereby reveals the meaning of ageing for dormant yeast spores and shows that they die when their gene-expressing ability is irreversibly lost. HighlightsO_LIFor a given glucose concentration, a dormant yeast spore has a well-defined probability of germinating ("germination ability"). C_LIO_LIA spores germination ability positively correlates with its RNAP I-III levels and the gene-expression (GFP) level it can realize when the expression is forced without nutrients. C_LIO_LIAgeing during dormancy means gradual decreases in germination ability, RNAP levels, and GFP-level realizable when expression is forced. C_LIO_LISpores die after sufficiently losing gene-expressing ability and drugs that inhibit gene expression during dormancy shorten spores lifespans (e.g., from months to a day). C_LI

systems biology↗

bioRxiv2019

Cells reshape habitability of temperature by secreting antioxidants to help each other replicate and avoid population extinction

How the rising global temperatures affect organisms is a timely question. The conventional view is that high temperatures cause microbes to replicate slowly or die, both autonomously. Yet, microbes co-exist as a population, raising the underexplored question of whether they can cooperatively combat rising temperatures. Here we show that, at high temperatures, budding yeasts help each other and future generations of cells replicate by secreting and extracellularly accumulating glutathione - a ubiquitous heat-damage-reducing antioxidant. Yeasts thereby collectively delay and can halt population extinctions at high temperatures. As a surprising consequence, even for the same temperature, a yeast population can either exponentially grow, never grow, or grow after unpredictable durations (hours-to-days) of stasis, depending on its population density. Despite the conventional theory stating that heat-shocked cells autonomously die and cannot stop population extinctions, we found that non-growing yeast-populations at high temperatures - due to cells cooperatively accumulating extracellular glutathione - continuously decelerate and can eventually stop their approach to extinction, with higher population-densities stopping faster. We show that exporting glutathione, but not importing, is required for yeasts to survive high temperatures. Thus, cooperatively eliminating harmful extracellular agents - not glutathiones actions inside individual cells - is both necessary and sufficient for surviving high temperatures. We developed a mathematical model - which is generally applicable to any cells that cooperatively replicate by secreting molecules - that recapitulates all these features. These results show how cells can cooperatively extend boundaries of life-permitting temperatures.

systems biology↗

bioRxiv2019

Cellular dialogues that enable self-organization of dynamic spatial patterns

Cells form spatial patterns by coordinating their gene expressions. How a group of mesoscopic numbers (hundreds-to-thousands) of cells, without pre-defined morphogens and spatial organization, self-organizes spatial patterns remains incompletely understood. Of particular importance are dynamic spatial patterns - such as spiral waves that perpetually move and transmit information over macroscopic length-scales. We developed an open-source, expandable software that can simulate a field of cells communicating with any number of cell-secreted molecules in any manner. With it and a theory developed here, we identified all possible \"cellular dialogues\" - ways of communicating with two diffusing molecules - and core architectures underlying them that enable diverse, self-organized dynamic spatial patterns that we classified. The patterns form despite widely varying cellular response to the molecules, gene-expression noise, and spatial arrangement and motility of cells. Three-stage, \"order-fluctuate-settle\" process forms dynamic spatial patterns: cells form long-lived whirlpools of wavelets that, through chaos-like interactions, settle into a dynamic spatial pattern. These results provide a blueprint to help identify missing regulatory links for observed dynamic-pattern formations and in building synthetic tissues.

systems biology↗

bioRxiv2017

Out-of-equilibrium statistical dynamics of spatial pattern generating cellular automata

How living systems generate order from disorder is a fundamental question1-5. Metrics and ideas from physical systems have elucidated order-generating collective dynamics of mechanical, motile, and electrical living systems such as bird flocks and neuronal networks6-8. But suitable metrics and principles remain elusive for many networks of cells such as tissues that collectively generate spatial patterns via chemical signals, genetic circuits, and dynamics representable by cellular automata1,9-11. Here we reveal such principles through a statistical mechanics-type framework for cellular automata dynamics in which cells with ubiquitous genetic circuits generate spatial patterns by switching on and off each others genes with diffusing signalling molecules. Lattices of cells behave as particles stochastically rolling down a pseudo-energy landscape - defined by a spin glass-like Hamiltonian - that is shaped by \"macrostate\" functions and genetic circuits. Decreasing the pseudo-energy increases the spatial patterns orderliness. A new kinetic trapping mechanism - \"pathway trapping\" - yields metastable spatial patterns by preventing minimization of the particles pseudo-energy. Noise in cellular automata reduces the trapping, thus further increases the spatial order. We generalize our framework to lattices with multiple types of cells and signals. Our work shows that establishing statistical mechanics of computational algorithms can reveal collective dynamics of signal-processing in biological and physical networks.

biophysics↗