Speaker: Xiangyu Yao (Jacky), GBCB Doctoral Candidate
Title: Robustness of Oscillations in Models of the Mammalian Circadian Clock
Abstract: The circadian rhythm aligns bodily functions to the day/night cycle and is important for our health. The rhythm originates from an intracellular, molecular clock mechanism that mediates rhythmic gene expression. It is long understood that transcriptional negative feedback with sufficient time delay is key to generating circadian oscillations. However, some of the most widely cited mathematical models for the circadian clock suffer from problems of parameter ‘fragilities’. That is, sustained oscillations are possible only for physically unrealistic parameter values. A recent model by Kim and Forger nicely incorporates the inhibitory binding of PER2, a key clock protein, to its transcription activator BMAL1, but oscillations in their model require a binding affinity between PER2 and BMAL1 that is orders of magnitude larger than observed binding affinities of protein complexes. To rectify this problem, we make several physiologically credible modifications to the Kim-Forger model, which allow oscillations to occur with more realistic binding affinities. The modified model is further extended to explore the potential roles of supplementary feedback loops in the mammalian clock mechanism. Ultimately, accurate models of the circadian clock will provide better predictive tools for chronotherapy and chrono-pharmacology studies
Speaker: Sean McMahon, VT
Date and place: Wednesday, June 21, 4:00-5:00 pm
Title: Mechanical limitations of Clostridium perfringens chains
Abstract: Many bacteria species are able to expedite colony expansion through motility of the cells. Clostridium perfringens, the primary cause of lethal gas gangrene, exhibits a unique mode of colony expansion on a substrate surface that, surprisingly, does not depend on motility in single cells. Specifically, daughter cells maintain end-to-end connections after cell division, amounting to long chains of cells that continuously elongate as individual cells grow and divide. Such cell growth-driven motility would accelerate as cell divisions increase the number of cells in a chain, and the tip of a long chain could potentially reach a very high speed. However, in this work we constructed a mechanical model to show that the efficacy of such growth-driven motility is limited by the buildup of mechanical stresses at the cell-cell joints. Specifically, our model depicts the growth of the bacterial chains based on the cell growth, strength of connections between cells, and drag forces from the substrate. Our model shows that stress at the joints between adjacent cells increases exponentially as the cell chain grows, making long chains prone to breakage. We further performed a perturbation analysis to estimate the critical stress leading to chain breakage and its dependence on the mechanical attributes and cell growth rate. Based on this critical breaking stress, we were able to estimate the physical limits of the elongation rate of a single cell chain, and found it to fall short of the rate at which wild C. perfringens can penetrate patient tissues. Finally, the model suggests additional mechanisms that can help C. perfringens chains delay breakage and thereby achieve a higher expansion rate.
Speaker: Xiangyu (Jacky) Yao, GBCB Doctoral Candidate
Advisor: Dr. Jing Chen, Biological Sciences at VT
Title: Critical Role of Deadenylation in Regulating Poly(A) Rhythms and Circadian Gene Expression
The mammalian circadian clock is deeply rooted in rhythmic regulation of gene expression. Rhythmic transcriptional control mediated by the circadian transcription factors is thought to be the main driver of mammalian circadian gene expression. However, mounting evidence has demonstrated the importance of rhythmic post-transcriptional controls, and it remains unclear how the transcriptional and post-transcriptional mechanisms collectively control rhythmic gene expression.
In mouse liver, hundreds of genes were found to exhibit rhythmicity in poly(A) tail length, and the poly(A) rhythms are strongly correlated with the protein expression rhythms. To understand the role of rhythmic poly(A) regulation in circadian gene expression, we constructed a parsimonious model that depicts rhythmic control imposed upon basic mRNA expression and poly(A) regulation processes, including transcription, deadenylation, polyadenylation, and degradation. The model results reveal the rhythmicity in deadenylation as the strongest contributor to the rhythmicity in poly(A) tail length and the rhythmicity in the abundance of the mRNA subpopulation with long poly(A) tails (a rough proxy for mRNA translatability).
In line with this finding, the model further shows that the experimentally observed distinct peak phases in the expression of deadenylases, regardless of other rhythmic controls, can robustly cluster the rhythmic mRNAs by their peak phases in poly(A) tail length and abundance of the long-tailed subpopulation. This provides a potential mechanism to synchronize the phases of target gene expression regulated by the same deadenylases. Our findings highlight the critical role of rhythmic deadenylation in regulating poly(A) rhythms and circadian gene expression.
Yao X, Kojima S and Chen J, Critical role of deadenylation in regulating poly(A) rhythms and circadian gene expression (2020) PLoS Computation Biology, 16(4): e1007842.
Speaker: Sean McMahon, VT
Date and place: Wednesday, April 1, 1:15-2:15 pm
Title: Modeling growth-mediated motility in Clostridium perfringens
Abstract: Many bacteria species are able to expedite colony expansion through motility of the cells. Clostridium perfringens, the primary cause of lethal gas gangrene, exhibit a unique mode of colony expansion. Chains of cells continuously grow outward from the bacterial colony and curve. These bacteria appear to lack a direct motility mechanism in individual cells, and are hypothesized to rely on bacterial growth to push adjacent cells in the strongly connected cell chains. Interestingly, these cell chains tend to curve as they grow. Using a “rigid-rod” model we simulate the growth dynamics of these bacteria chains. Our preliminary results suggest that the cell chain curvature cannot result from growth of the cell chain and its interaction with the substrate. Motivated by the observation that multiple chains growing side-by-side appear to curve more than single chains, we hypothesize that chain curvature may be a result of lateral interactions between cell chains. An expanded version of the rigid-rod model is used to include these lateral interactions and also implements collision dynamics between cells in adjacent chains. Ultimately, we will use these mathematical models to investigate if this expansion mode of C. perfringens could be advantageous for spreading and surviving on different substrates and environments the bacteria may encounter during their opportunistic life cycle.
Li X#, Gonzalez F#, Esteves N, Scharf BE* and Chen J*, Formation of Phage Lysis Patterns and Implications on Co-Propagation of Phages and Motile Host Bacteria. (2020) PLoS Computation Biology, 16(3):e1007236. (# Co-first authors. * Co-corresponding authors)