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 S13: Physics of Genome Organization IFocus Live
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Sponsoring Units: DBIO Chair: Alexandre Morozov, Rutgers Univ, New Brunswick; Bin Zhang, Massachusetts Institute of Technology MIT |
Thursday, March 18, 2021 11:30AM - 12:06PM Live |
S13.00001: Strategies transcription factors use to gain access to nucleosomal DNA Invited Speaker: Michael Poirier expert |
Thursday, March 18, 2021 12:06PM - 12:18PM Live |
S13.00002: Three-dimensional modeling dynamics of nuclear organization Rabia Laghmach, Michele Di Pierro, Davit Potoyan The eukaryotic genome' intranuclear order is physically established through the hierarchical compartmentalization of nuclear chromatin, which is strongly coupled with gene regulatory activities. The mechanistic underpinnings of chromatin compartmentalization, its dynamics, and its impact on gene regulatory processes are, however, still poorly understood. Understating the principles that control the dynamics and the spatial regulation of chromatin droplets formation is a possible way to elucidate the relationship between chromatin compartmentalization patterns and gene regulation. Here, we present a multiphasic liquid model of nucleus to study the 3D chromatin organization dynamics. The model accounts for various subcompartments chromatin interactions as well as differential interactions between heterochromatin and nuclear Lamina, and dynamically nuclear geometry change. We show the ability of our model to predict various nuclear morphologies at a large-length scale depending on the cell types and stages of the life-cycle of cells. Comparing the imaging experiments and 3D simulations of the example of a genetic Drosophila nucleus has demonstrated excellent agreement. |
Thursday, March 18, 2021 12:18PM - 12:30PM Live |
S13.00003: Decoding DNA Barcodes using a Double-Nanopore System Swarnadeep Seth, An Vuong, Walter Reisner, William Dunbar, Aniket Bhattacharya DNA barcode detection has imporatnt applications in conservation biology, taxonomy research, identifying disease vectors, authenticating herbal products, and unambiguously labeling food specimens. Recent experiments (Dekker et al., Nano Lett. 2016; X. Liu et al., Small 2019) explored the possibilities of determining sequences with greater accuracy by ``flossing” the DNA multiple times through multi-nanopore systems. We use Brownian dynamics simulation to study a model coarse-grained dsDNA threading through a double-nanopore setup. Several markers/tags are annexed along the dsDNA replicating the barcodes studied experimantally. The DNA segment containing the barcodes is scanned several hundred times using an alternating bias present in each pore. The separation among the markers (barcodes) is calculated using the velocity and time of arrival of the markers in respective pores during the chain’s motion from left to right pore and vice versa. However, our studies clearly show that a straight forward method underestimates barcode separation due to chain’s non-monotonic velocity profile. We propose alternative method to rectify this which we believe is relevant for experiments. |
Thursday, March 18, 2021 12:30PM - 12:42PM Live |
S13.00004: Mechanical Control of Transcriptional Elongation by DNA Supercoiling Shubham Tripathi, Sumitabha Brahmachari, Jose N Onuchic, Herbert Levine Transcriptional elongation by an RNA polymerase II (RNAP) positively supercoils (overtwists) the downstream DNA and negatively supercoils (untwists) the upstream DNA. The resultant DNA torsional stress, if not relaxed quickly, can hinder transcriptional elongation. Recent experiments have shown that multiple RNAPs transcribing a gene may cooperate by neutralizing the supercoils generated by their neighbors. Here, we describe a theoretical model that couples RNAP motion and DNA torsional response, and use the model to predict the RNAP velocity on stretched and / or twisted DNA. Using stochastic simulations, we demonstrate long-range cooperation between multiple RNAPs transcribing a gene, and find that inhibiting transcription initiation can slow down the RNAPs already recruited. Further, we investigate the coupling between RNAPs transcribing genes in different orientations— tandem, divergent, and convergent— and report that our model predictions agree with experimental observations. Our model thus provides key insights into how DNA supercoiling can regulate transcriptional elongation and makes new predictions that can be tested in future experiments. |
Thursday, March 18, 2021 12:42PM - 12:54PM Live |
S13.00005: Dynamic nuclear structure emerges from chromatin crosslinks and motors Kuang Liu, Alison Patteson, Edward J Banigan, J M Schwarz The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity and crosslinks. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, crosslinking, and chromosome-lamina binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system. |
Thursday, March 18, 2021 12:54PM - 1:06PM Live |
S13.00006: Aberrant CTCF binding facilitates phase-separated transcriptional condensate formation in cancer Zhenjia Wang, Chongzhi Zang CCCTC-binding factor (CTCF) is a transcription factor (TF) that induces DNA looping and functions as a chromatin insulator. Disruption of CTCF binding associated with DNA methylation changes have been reported in many cell systems that can result in aberrant chromatin interaction and dysregulation of gene expression. Using an integrative data science approach, we systematically analyzed hundreds of CTCF ChIP-seq datasets and other genomic big data across different human tissues and cancer samples and identified cancer-specific patterns of gained and lost CTCF binding in several cancer types. We found that cancer-specific CTCF binding events do not always arise from changes in DNA methylation or sequence mutations. Instead, CTCF binding can be recruited by clusters of transcription factor and co-factor molecules in the formation of phase-separated transcriptional condensates at super-enhancers in cancer. CTCF plays an instrumental role in maintaining the active chromatin state with the transcriptional condensates, to facilitate oncogenic transcriptional activation. This work indicates a novel function of CTCF in cancer gene expression program controlled by transcriptional condensates. |
Thursday, March 18, 2021 1:06PM - 1:18PM Live |
S13.00007: Piercing Mechanism of Biological Nano-injection Machines Ameneh Maghsoodi, Noel C Perkins Mechanical injection, a process of material delivery into living cells using a needle, is a fundamental technique for a variety of applications in biology and medicine including single-cell transfection and drug delivery. To generate genetically modified cells with desired functions, developing an efficient injection technique capable of precise delivery of genomes into host cells without any damage to intracellular organelles is required. Designing such an efficient injection device can be inspired from biological injection machines including contractile bacteriophages. Contractile phages are remarkable nano-scale injection machines that kill competing bacteria by rupturing cell membrane and injecting their genome into the host. Since the structure and function of phages have been honed to perfection by millions of years of evolution, any engineered injection system mimicking the injection mechanism of bacteriophages is likely to be successful. A key step is to understand the structure and function of the bacteriophages. We propose a dynamic model of contractile phages to elucidate how they work in real-time. The model reveals the predictions of the dynamics, energetics, and mechanism of the injection machine and common physical principles underlying their injection process. |
Thursday, March 18, 2021 1:18PM - 1:54PM Live |
S13.00008: Molecular switch control of nucleic-acid processing machines Invited Speaker: Yann Chemla Single-molecule techniques have revolutionized our understanding of the mechanics and dynamics of DNA and of the molecular machines that process it. In this talk, I will discuss our work developing new single-molecule methods and integrating them with computational approaches to provide unprecedented access into the mechanisms of these molecular machines. I will discuss various applications of these approaches, in particular our measurements of helicases, which use the energy of ATP hydrolysis to separate the strands of nucleic acid duplexes and are essential components of the cellular machinery that maintains and repairs the genome. Our work shows how prototype members of helicases process DNA and possess molecular switches that regulate their activity. Interactions with protein partners are likely to provide control over these switches and thus the roles the helicases play. Our findings provide new insights on the mechanisms by which these molecular machines function and are regulated in the cell. |
Thursday, March 18, 2021 1:54PM - 2:06PM Live |
S13.00009: Inference of emergent spatio-temporal processes in single-cell genomics Fabrizio Olmeda, Tim Lohoff, Stephen J. Clark, Laura Benson, Felix Krueger, Wolf Reik, Steffen Rulands During early development, when the first cell fate decisions are made, the genome undergoes large-scale changes in the primary layer of epigenetic modifications, DNA methylation. Combining novel methods from genomics with bioinformatics and non-equilibrium physics, we show that the establishment of DNA methylation is a collective phenomenon involving feedback ranging over large genomic domains. Surprisingly, we found that de-novo methylation follows universal dynamics that is self-similar in time and independent of the genomic context. We capture these findings in a mechanistic model of de-novo methylation. By mapping our model to a quantum field theory, we show how these epigenetic marks are established through the cooperative action of DNMT3 enzymes exhibiting long-range interactions and leading to genome-wide collective dynamics. Theoretical predictions are tested on extensive time-resolved sequencing data. Our work sheds new light on epigenetic mechanisms involved in cellular decision making, predicting the formation of condensates of methylation in the nucleus. It also highlights how mechanistic insights into the molecular processes governing cell-fate decisions can be gained by the combination of novel methods from genomics and non-equilibrium physics. |
Thursday, March 18, 2021 2:06PM - 2:18PM Live |
S13.00010: Malleable DNA knot translocation in single-digit nanopores Rajesh Sharma, Ishita Agrawal, Liang Dai, Patrick Doyle, Slaven Garaj Knots in long DNA molecules, prevalent in vivo, serve as a model for studying the properties of biopolymers. Here, using solid-state nanopores, we study the translocation dynamics of knots in 48.5 kbp long lambda DNA molecules in a new regime of nanoscale confinement, large driving forces applied over short timescales. We demonstrate that DNA knots translocate in an isomorphic fashion, typically retaining their morphology by quickly compressing laterally once captured in the nanopore. We see an absence of knot tightening and jamming, and only a scant effect of sliding of knots in small nanopores of 5 nm diameter. We understand the observed malleability of knots using full-atom molecular dynamics simulations that reveal a transient, localized melting of strands in the high bending regime. Our results are useful for understanding DNA packaging and regulation in vivo, physics of biopolymers under nanoconfinement, and the development of sequencing technologies based on nanopores. |
Thursday, March 18, 2021 2:18PM - 2:30PM Live |
S13.00011: THE EFFECT OF GENOME SIZE ON THE STRUCTURE OF VIRAL SHELLS Sanaz Panahandeh, Siyu Li, Roya Zandi The self-assembly of virus particles in which the protein subunits encapsulate genome into a shell called the capsid is an essential step in the viral life cycle. This process is basically driven by the electrostatic interaction between positively charged protein subunits and negatively charged genome. We develop a model to investigate the impact of genome size on the structure of capsids. The results show that not only the size of the genome, but also the strengths of interactions between the genome and protein subunits affect the structure of closed capsids. Furthermore, We study the interplay between mechanical properties of proteins and the interaction between the genome and capsid. |
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