Bulletin of the American Physical Society
APS March Meeting 2020
Volume 65, Number 1
Monday–Friday, March 2–6, 2020; Denver, Colorado
Session R26: Physics of Genome Organization: From DNA to Chromatin: IFocus
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Sponsoring Units: DBIO DPOLY GSNP Chair: Alexandre Morozov, Rutgers University, New Brunswick Room: 403 |
Thursday, March 5, 2020 8:00AM - 8:36AM |
R26.00001: Strategies transcription factors use to gain access to nucleosomal DNA Invited Speaker: Michael Poirier The physical organization of all eukaryotic genomes is evolutionarily conserved. Histone protein octamers repeatedly wrap genomic DNA into nucleosomes to form long chromatin fibers. Nucleosomes and chromatin function to control accessibility of transcription factors to their DNA target sites, while transcription factors target DNA sites to active transcription by “opening up” chromatin. However, the dynamic interplay between transcription factor binding and nucleosome/chromatin DNA compaction is poorly understood at the mechanistic level. I will discuss proposed strategies for how transcription factors bind to their sites within compact chromatin, and the differences between activating and pioneering transcription factors. I will then present our recent single molecule studies on how nucleosomes have profoundly different impacts on the DNA binding and dissociation dynamics of these two types of transcription factors. Our finds provide a potential way to define the functional differences between activating and pioneering transcription factors. |
Thursday, March 5, 2020 8:36AM - 8:48AM |
R26.00002: Theory and modeling of active nucleosome repositioning Zhongling Jiang, Bin Zhang Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-templated processes. Its establishment in vivo is significantly influenced by ATP driven remodeling enzymes and transcription, which involves remodeler recruitment. On one hand, the non-equilibrium nature of remodelers has hindered the development of a unified theoretical framework for nucleosome positioning. On the other hand, explicit models are lacking in explaining the impact of transcription levels on nucleosome positioning since the complicated transcription process. For remodeling enzymes, we use a perturbation theory to show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Our theory provides an intuitive understanding for the impact of remodelers. By combining remodelers and RNAP II, we developed a transcription model, which illustrates opposite trends of nucleosome positioning patterns changing with transcription levels in yeasts and higher animals. This explanation qualitatively reproduces the experimental nucleosome positioning patterns. |
Thursday, March 5, 2020 8:48AM - 9:00AM |
R26.00003: Centromeres and Telomeres as Rheological Probes of the Human Nucleus Alexis Clavijo, Steven Ionov, Alexandra Zidovska The nucleus of eukaryotic cells stores genetic information in chromatin, the functional form of |
Thursday, March 5, 2020 9:00AM - 9:12AM |
R26.00004: Knot dynamics of a DNA strand pushed inside a nanochannel Jan Rothörl, Peter Virnau, Aniket Bhattacharya We investigate knot formation for a model DNA polymer pushed inside a square nanochannel whose width is much shorter compared to the contour length of the chain using Brownian dynamics simulation. |
Thursday, March 5, 2020 9:12AM - 9:24AM |
R26.00005: Error-speed correlations in biopolymer synthesis Simone Pigolotti, Davide Chiuchiu, Yuhai Tu Synthesis of biopolymers such as DNA, RNA, and proteins are biophysical processes aided by enzymes. Performance of these enzymes is usually characterized in terms of their average error rate and speed. However, because of thermal fluctuations in these single-molecule processes, both error and speed are inherently stochastic quantities. We study fluctuations of error and speed in biopolymer synthesis and show that they are in general correlated. This means that, under equal conditions, polymers that are synthesized faster due to a fluctuation tend to have either better or worse errors than the average. The error-correction mechanism implemented by the enzyme determines which of the two cases holds. For example, discrimination in the forward reaction rates tends to grant smaller errors to polymers with faster synthesis. The opposite occurs for discrimination in monomer rejection rates. Our results provide an experimentally feasible way to identify error-correction mechanisms by measuring the error-speed correlations |
Thursday, March 5, 2020 9:24AM - 9:36AM |
R26.00006: Noninvasive Measurement of Interphase Chromatin Rheology In Vivo Iraj Eshghi, Jonah Eaton, Alexandra Zidovska Material properties of the genome are critical for its proper function and organization inside |
Thursday, March 5, 2020 9:36AM - 9:48AM |
R26.00007: A Mechanochemical Model of Transcriptional Bursting Alena Klindziuk, Billie Meadowcroft, Anatoly Boris Kolomeisky Variability in gene expression ensures that cells with the same genotype always exhibit different phenotypes. Transcription bursting, or the random interruptions in the production of messenger RNA molecules, is one probable cause of this ubiquitous variability. Yet, the molecular mechanisms behind the bursting behavior remain unclear. Recent studies suggest that DNA supercoiling, which occurs during transcription, might be directly related to the bursting behavior. Stimulated by these observations, we developed a stochastic mechano-chemical model of supercoiling-induced transcriptional bursting. Using thermodynamically consistent coupling between mechanical and chemical processes, dynamic properties of transcription are explicitly evaluated. Theoretical analysis shows that the transcription bursting is observed when both supercoiling and the mechanical stress-release due to an enzyme gyrase are present in the system. A comparison with experimental data on bacteria allowed us to evaluate the energetic cost of supercoiling during transcription. We find that a relatively weak mechano-chemical coupling allows transcription to be regulated most effectively. |
Thursday, March 5, 2020 9:48AM - 10:00AM |
R26.00008: Field theoretic methods applied to epigenetic models Amogh Sood, Bin Zhang Chromosomal regions are known to adopt stable, heritable states which result in bistable gene expression without changes to the underlying DNA sequence. Such epigenetic control is a consequence of covalent modifications of histones. We introduced a (0+1)-dimensional kinetic model, wherein modified nucleosomes recruit enzymes that similarly modify neighbouring nucleosomes, to investigate the stability and heritability of the states. To make the model analytically tractable, we used the Doi-Peliti formalism, a second quantized description of the underlying master equation of a stochastic process such as the epigenetic problem at hand, that makes it amenable to attack via path integral methods such as semi-classical approximations, perturbation theory and renormalization group. Our model exhibits bistability, and using minimum action methods we can compute escape paths and probabilities between the two stable states. We are now coupling the model with a gene switch to quantify the developmental landscape of cell differentiation. |
Thursday, March 5, 2020 10:00AM - 10:12AM |
R26.00009: Pulling a DNA through a Double-Nanopore system: A Brownian Dynamics Study Peter Smucz, Swarnadeep Seth, Aniket Bhattacharya We study translocation of a model DNA polymer captured in a double nanopore (DNP) system using Brownian dynamics (BD). We consider two different configurations as reported in recent experimental studies. In the first case, the direction of translocation is parallel to the vector connecting the two pores (X. Liu et al., Small 2019, 1901704). In the second case, the direction of translocation is perpendicular to the vector connecting the two pores (S. Pud et al., Nano Lett. 2016, 16, 8021-8028). In the former case we demonstrate that in the absence of a time dependent feedback mechanism, the velocity of the segment in between the pores is not constant, which hinders the mapping of the data from the time domain into genomic length. In the second case, we investigate parameters for optimal translocation of the chain through the DNP system. We consider limiting cases, where the distance between the pores is much shorter than the contour length of the chain, and show that one can use scaling results for single nanopore translocation to interpret results for the DNP translocation. |
Thursday, March 5, 2020 10:12AM - 10:24AM |
R26.00010: Loop extrusion in chromatin: A question of time! Ajoy Maji, Ranjith Padinhateeri, Mithun Kumar Mitra One important question in the context of the 3D organization of chromosomes is the mechanism of formation of large loops between distant base pairs. Recent experiments suggest that the formation of loops might be mediated by Loop Extrusion Factors like cohesin. Experiments of cohesin have shown that cohesins walk diffusively on the DNA and nucleosomes act as obstacles to the diffusion, lowering the permeability and hence lowering the effective diffusion constant. An estimation of the times required to form the loops of typical sizes seen in Hi-C experiments using these low effective diffusion constants leads to times that are unphysically large. The puzzle then is the following, how does a cohesin molecule diffusing on the DNA backbone achieve speeds necessary to form the large loops seen in experiments? We propose a simple physical answer to this puzzle and show how a naive obstacle view of nucleosomes can be misleading. |
Thursday, March 5, 2020 10:24AM - 10:36AM |
R26.00011: Structural and Dynamical Signatures of Local DNA Damage in Live Cells Jonah Eaton, Alexandra Zidovska The dynamic organization of chromatin inside the cell nucleus plays a key role in gene regulation and maintaining genome integrity. While the static folded state of the genome has been studied before, the dynamical signatures of processes such as transcription or DNA repair are unknown. We investigate the interphase chromatin dynamics in human cells in response to local damage, DNA double strand breaks (DSBs), by monitoring the DSB dynamics and the compaction of the surrounding chromatin in live cells. We find DSBs to possess a unique chromatin compaction profile, while being more mobile when located in the nuclear interior as opposed to the periphery. We show that DSB motion is subdiffusive, ATP-dependent, and exhibits unique dynamical signatures compared to undamaged chromatin. We find that DSB mobility follows a universal relationship based on the local environment suggesting that the repair processes are robust and likely deterministic. Such knowledge may help in detection of DNA damage in live cells and aid our biophysical understanding of genome integrity in health and disease [Eaton & Zidovska, Biophys. J., 2019]. |
Thursday, March 5, 2020 10:36AM - 10:48AM |
R26.00012: Extracting the degree of order in the bacterial chromosome using statistical physics Joris Messelink, Jacqueline Janssen, Muriel van Teeseling, Martin Thanbichler, Chase Broedersz Elucidating the three-dimensional spatial organization of the bacterial chromosome is essential to understand how genomic processes are spatially regulated inside the cell. Recent Hi-C chromosome conformation capture experiments provide contact frequency maps of the chromosome. These experiments reveal structural organization beyond that of an amorphous polymer. However, despite such experimental advances, the degree of spatial organization of the bacterial chromosome remains unclear. To investigate this, we develop a maximum entropy approach to extract the three-dimensional structure of the bacterial chromosome from such data. Using this approach, we obtain a coarse-grained model for the full distribution of chromosome configurations for the bacterium C. crescentus. We validate the predictive power of our model by experiments on the localization of chromosomal loci in the cell. Our model reveals novel features of spatial chromosome organization on various length scales. Our approach is not organism-specific, and opens up a new way of analyzing spatial chromosome organization. |
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R26.00013: Direct Quantification of Gene Regulation by Transcription-Factor Binding at an Endogenous Gene Locus Jingyao Wang, Yijing Dong, Huihan Bao, Xintao Yao, Anna Marie Sokac, Ido Golding, Heng Xu Gene activity is controlled by the binding of transcription factors (TFs) to the regulatory sequence of the gene, yet a direct in situ mapping from TF binding to mRNA production of a single gene remains elusive, due to the difficulty of capturing individual TF binding events of a specific gene from the ocean of TF signal in cell nucleus. Here we combine single-molecule fluorescent imaging of protein, mRNA, and gene loci to detect and quantify distinct binding configurations of multiple TFs and epigenetically modified histones, as well as the resulting nascent mRNAs at endogenous hunchback (hb) gene loci in early Drosophila embryos. Using stochastic theoretical analysis, we show that TF binding follows nonequilibrium multi-state kinetics, breaking the law of mass action. hb transcription activation is a multi-step process initiated by transient binding of the Bicoid transcription factor. Unlike TF binding at hb, the histone signal is deprived at active gene loci, indicating that nucleosome unwinding is necessary for gene activation. Our method provides a general framework to decipher the dynamics of complex gene regulatory networks in situ. |
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