Bulletin of the American Physical Society
APS March Meeting 2021
Volume 66, Number 1
Monday–Friday, March 15–19, 2021; Virtual; Time Zone: Central Daylight Time, USA
Session X14: Dynamics of Gene RegulationLive
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Sponsoring Units: DBIO Chair: Sarah Marzen; Huy Vo, Colorado State University |
Friday, March 19, 2021 8:00AM - 8:12AM Live |
X14.00001: Three Pillars to Stochastic Control: Autoregulation, Noise and Feeback Michael May, Brian Munsky Synthetic biology seeks to develop modular bio-circuits that combine to produce complex, controllable behaviors. Modern synthetic biology design processes have focused to create robust components to mitigate the noise of gene expression and reduce the heterogeneity of single-cell responses. However, deeper understanding of noise can achieve control goals that would otherwise be impossible. We explore how an “Optogenetic Maxwell Demon” could selectively amplify noise to control multiple cells using single-input-multiple-output (SIMO) feedback. Using data-informed [1] stochastic model simulations and theory, we show how an appropriately selected stochastic SIMO controller can drive multiple different cells to different user-specified configurations irrespective of initial condition [2]. We explore how controllability depends on cells’ regulatory structures, the number of cells controlled, the number of cells observed, and the accuracy of the model used. Our results suggest that gene regulation noise, when combined with optogenetic feedback and non-linear biochemical autoregulation, can synergize to enable precise control of complex stochastic processes. |
Friday, March 19, 2021 8:12AM - 8:24AM Live |
X14.00002: A Generalized Langevin Approach to Modeling Protein Migration Alana Bailey, Liam G. Stanton
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Friday, March 19, 2021 8:24AM - 8:36AM Live |
X14.00003: Stochastic transcription-error correction by backtracking and repelling RNA polymerases Xinzhe Zuo, Tom Chou Backtracking of RNA polymerase (RNAP) is an important pausing mechanism during DNA transcription that is part of the error correction process that enhances transcription fidelity. We model the backtracking mechanism of RNA polymerase which usually happens when the polymerase tries to incorporate a mismatched nucleoside triphosphate (NTP). Previous models have made assumptions for easier calculations. One of the key assumptions made is that there is no trailing polymerase behind the backtracking polymerase or the trailing polymerase remains stationary when the leading polymerase backtracks. We derive analytic solutions for a stochastic model that allows for locally interacting RNAPs to explicitly show how a trailing RNAP influences the probability that an error is corrected or incorporated by the leading backtracking RNAP. |
Friday, March 19, 2021 8:36AM - 8:48AM Live |
X14.00004: Restricted mobility and jamming of densely packed DNA exiting a viral capsid Mounir Fizari, Nicholas Keller, Douglas E Smith We probe the dynamics of single charged polymer molecules (DNA) under tight 3D confinement inside phage phi29 capsids by using optical tweezers to pull them out through portal nanochannels. At DNA packing densities higher than ~0.3 g/ml, we observe a sharp decrease in exit velocity, highly heterogenous dynamics, and long pauses. These findings are consistent with decreased molecular mobility and transient non-equilibrium jamming of polymer chain segments. Addition of Mg 2+ ions, which electrostatically screen DNA, decrease exit velocity and increase pause durations, consistent with decreased self-repulsion and increased self-friction between strands. Preliminary measurements with varying applied and internal forces suggest that, contrary to prior hypothesis, exit velocity may not be linearly proportional to driving force as expected for a process governed only by simple viscous friction. |
Friday, March 19, 2021 8:48AM - 9:00AM Live |
X14.00005: Switch-like mRNA localization to mitochondria arises from nonequilibrium protein translation effects Aidan Brown, Ximena Garcia-Arceo, Tatsuhisa Tsuboi, Brian Zid, Elena Koslover Many mitochondrial genes are encoded in the nucleus, translated in the cytosol, and the proteins imported into mitochondria. In yeast, the fraction of cell volume occupied by mitochondria changes with growth conditions. Some nuclear-encoded mRNA switch from low to high mitochondrial localization as the mitochondrial volume fraction increases, while the localization of other genes remains consistently low or high. mRNA can be effectively tethered to mitochondria via the mitochondrial import of nascent, incompletely translated polypeptides, enhancing mitochondrial localization. To understand the distinct localization behaviours for mRNA of nuclear-encoded mitochondrial genes, we use a quantitative model of mRNA diffusion around the cell, protein translation along mRNA, and nascent polypeptide tethering. Using this model, we explain how the nonequilibrium nature of protein translation combines with asymmetric diffusive search times to allow for switch-like, consistently low, or consistently high mitochondrial localization. |
Friday, March 19, 2021 9:00AM - 9:12AM Live |
X14.00006: Live measurements of transcriptional bursting and dynamic gene regulation in early fly embryos Po-Ta Chen, Benjamin Zoller, Michal Levo, Thomas Gregor Gene regulation is intrinsically dynamic: from the microscopic molecular events underlying transcriptional bursting, to genes cross-regulating each other in the context of a genetic network during cellular fate specification. However, knowledge about the transcriptional dynamics of individual genes and the coordinated dynamics of multiple interacting genes in their endogenous context is almost completely missing. We have developed an optimized two-photon microscope to measure real-time gene activity in early fly embryos. Our data is highly quantitative making higher-order noise and cross-correlation analysis between multiple simultaneously measured genes possible. Focusing on the gap-gene-network in the early fly embryo, we measure endogenous transcriptional output of individual, and multiple genes simultaneously to test a novel time-dependent mathematical framework for transcriptional bursting dynamics and link these to transcriptional states at the network level. We are addressing two questions in particular: What are the dynamics of transcriptional bursting for individual genes? And how do the complex out-of-equilibrium dynamics of individual genes affect the dynamics of the gene regulatory network as a whole? |
Friday, March 19, 2021 9:12AM - 9:24AM Live |
X14.00007: A computational framework to study single-molecule canonical and non-canonical translation dynamics. Luis Aguilera, William Raymond, Amanda Koch, Kenneth Lyon, Tatsuya Morisaki, Timothy J. Stasevich, Brian Munsky Advances in fluorescence microscopy allow the direct visualization of gene expression with single-molecule resolution in live cells. Here, we combine fluorescence microscopy and stochastic modeling to study canonical and non-canonical ribosomal translation processes. Recent findings by our groups allowed us to conduct an extensive computational study of mRNA-translation at single-codon resolution in a large database of human genes. We integrated the results from this study in a software package rSNAPsim (Aguilera, et al., 2019, Plos Comp Biol). In a second study, we quantified ribosomal frameshifting in live cells at single-molecule resolution. Experimental data and simulations proved that frameshifting is a rare process occurring in ~8% of the studied proteins, occurring in long-lasting (~40min) bursting episodes (Lyon, et al., 2019. Mol Cell). More recently, our groups used a bicistronic biosensor to measure Cap-dependent and IRES-mediated initiation. We obtained that under normal conditions CAP initiation is ~ 3 times stronger than IRES initiation, but this proportion is dramatically altered during stress conditions that mimic viral infection (Koch, et al., Nat Struct Mol Biol 2020). |
Friday, March 19, 2021 9:24AM - 9:36AM Live |
X14.00008: Rationalizing the abundance statistics of feed-forward loop motifs: an evolutionary strategy mediated by control on fluctuations Md Sorique Aziz Momin, Ayan Biswas Bacteria rely on gene-transcription regulatory network motifs to harness dynamic environmental signals, crucial for their continued sustenance in evolutionary time-scales. Feed-forward loop (FFL) is the only motif naturally selected from a set of several random patterns and even within this group, there are only two out of possible eight motifs, which are statistically abundant. These circuits are indispensable in controlling metabolism and chemotaxis in E. coli. We construct a theoretical framework hypothesizing the rationale behind this phenomenon. Motivated by the E. coli dual-reporter technique (Elowitz et. al., Science, 2002), we derive a closed-form analytical expression of extrinsic noise supplied by the coregulator to the target gene in a generic FFL. This size-independent metric clearly demonstrates contributions of promoter occupancy, cooperativity, time-scale separation, regulatory modality (activation / repression), expression levels, and signal integration logic (additive / multiplicative). We demonstrate that the abundant coherent and incoherent type-1 FFLs have the highest amount of extrinsic noise compared to other FFLs in both fixed and variable input gene-expression conditions. |
Friday, March 19, 2021 9:36AM - 9:48AM Live |
X14.00009: Diffusiophoresis of passive particles in the presence of protein patterns Andriy Goychuk, Beatrice Ramm, Alena Khmelinskaia, Philipp Blumhardt, Hiromune Eto, Kristina A. Ganzinger, Petra Schwille, Erwin Frey Living cells can redistribute and transport molecules via motor proteins, self-assembling cytoskeletal elements or self-organizing reaction-diffusion systems. These processes commonly rely on specific protein interactions. However, recent experiments have shown that pattern-forming reaction-diffusion systems, such as the E. coli MinDE protein system, may also redistribute a wide range of completely unrelated molecules. What is the underlying physical mechanism and its implications for biology? |
Friday, March 19, 2021 9:48AM - 10:00AM Live |
X14.00010: Jamming-free crowded transport through the nuclear pore complex Tiantian Zheng, Chad Gu, Anton Zilman The nuclear pore complex (NPC) is the main conduit for transporting materials into and out of the nucleus of eukaryotic cells. The central channel of the NPC is crowded with many simultaneously translocating cargoes. Crowding is known to slow down transport in many systems, requiring additional mechanisms to mitigate negative effects. Yet surprisingly, past experiments have shown that crowding can benefit cargo transport through the NPC, by increasing transport efficiency and decreasing transport time, thus avoiding jamming. We simulate an NPC mimic containing only the main components of the NPC system -- polymeric intrinsically disordered proteins (called FG nups) which line the NPC channel, and transport proteins which ferry cargoes across the FG nup assembly -- and their coarse-grained interactions with each other. We show that the regime of jamming-free transport is possible if (and only if) FG nups within the NPC are spatially arranged into “vestibule” and “barrier” regions, as previously suggested by experiments. Our analysis provides the first theoretical explanations for how crowding can benefit transport in the NPC, and suggests a functional reason for why the NPC internal spatial structure is evolutionarily conserved across species. |
Friday, March 19, 2021 10:00AM - 10:12AM Live |
X14.00011: Using genetic data to predict clinical outcomes in emergent antibody therapies against HIV. Colin LaMont, Jakub Otwinowski, Armita Nourmohammad Rapidly evolving pathogens such as tuberculosis, HIV, and influenza, pose a serious risk to global health. New interventions are in constant development, but just as quickly resistant traits emerge and become fixed in the pathogen population, rendering interventions ineffective. To frustrate the emergence of resistance, one can combine several interventions together. This combined approach underpins the success of modern HIV antiretroviral therapy and frontline tuberculosis treatment. |
Friday, March 19, 2021 10:12AM - 10:24AM Live |
X14.00012: Estimating the Role of Active Matter and Population Genetic Dynamics in Enhancing Antibiotic Resistance in Expanding Bacterial Colonies via Lattice Simulations Jimmy Gonzalez, Daniel A Beller, Arvind Gopinath The emergence of antibiotic resistance in bacterial cells remains a major issue in medical fields, with new strains resistant to nearly all available antibiotic medication frequently emerging. One important issue is the colonization of surfaces by species which exhibit collective motion known as swarming. Such systems have been observed to benefit from this collective motion by gaining enhanced antibiotic resistance through mechanisms such as segregation and necrosignaling from dead bacterial cells. In this work, we employ 2D lattice models combing population genetics and hydrodynamic interactions to study the effects of active matter dynamics on genetic structure in bacterial colonies, as well as statistically characterize the role that mixing, genetic drift, cell motility, and mutation have on the emergence of antibiotic resistance in active bacterial populations. By understanding how population structure is affected by active matter dynamics, we can understand the benefits of cell motility in swarms on adaptation and evolution. |
Friday, March 19, 2021 10:24AM - 10:36AM Live |
X14.00013: Trading bits in the readout from a genetic network Marianne Bauer, William S Bialek, Thomas Gregor, Mariela D Petkova, Eric F. Wieschaus In genetic networks, information of relevance to the organism is represented by the concentrations of transcription factor molecules. In order to extract this information the cell must effectively “measure” these concentrations, but there are physical limits to the precision of these measurements. We explore this trading between bits of precision in measuring concentration and bits of relevant information that can be extracted, using the gap gene network in the early fruit fly embryo as an example. We argue that cells in the fly embryo can extract all the available information about their position if the concentration measurements approach the physical limits to information capacity, and that realistic molecular mechanisms can reach these abstract bounds if their parameters are selected appropriately. |
Friday, March 19, 2021 10:36AM - 10:48AM Live |
X14.00014: Top-down analysis of gene-regulatory networks using global coordination method Eyal Atias, Guy Amit, Amir Bashan <div style="direction: ltr;">Cellular activity is governed by an underlying gene regulatory network. However, due to the large complexity of the regulatory network, inferring them is extremely challenging. A novel computational measure was recently developed to cut across the network of interactions among genes and consider their transcriptional interrelationships in a top-down manner. The new measure, called global coordination level (GCL), is based on the average multivariate dependency between the expression levels of random subsets of genes in single-cell RNA-seq datasets. Yet, there are several fundamental features of this top-down method that need addressing. Here, we systematically analyse the performance and limitations of the GCL using real and simulated gene expression data. We compare the results to other bottom-up methods, such as co-expression matrices and reconstructed networks. We find that the GCL has significant advantage in detecting the gene-to-gene coordination level, especially where the number of available samples is low compared to the number of genes, which is a typical scenario in current available data. The systematic analysis of the GCL provides a useful foundation for future application of this method.</div> |
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