Bulletin of the American Physical Society
APS March Meeting 2020
Volume 65, Number 1
Monday–Friday, March 2–6, 2020; Denver, Colorado
Session S26: Physics of Genome Organization: From DNA to Chromatin: IIFocus
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Sponsoring Units: DBIO DPOLY GSNP Chair: Alexandre Morozov, Rutgers University, New Brunswick Room: 403 |
Thursday, March 5, 2020 11:15AM - 11:51AM |
S26.00001: On the Border of Order: Chromosomal Organization in Space and Time Invited Speaker: Olga Dudko Many biological processes, from antibody production to tissue differentiation, share a common fundamental step — establishing a physical contact between distant genomic segments. How do remote segments find each other on a remarkably short timescale despite being strung out over millions of base pairs along the DNA? What is the mechanism of the high degree of orchestration of remote genomic interactions? We address these questions in the context of adaptive immunity – the system that enables the individual to respond to a great variety of pathogens through a diverse repertoire of antibodies. Experimental data from live-cell imaging in B-lymphocytes reveal the signatures of anomalous diffusion that help us identify the dominant mechanism of genomic motion. Comparison of experimental and simulated data, along with insights from polymer physics, suggest that an interphase chromosome behaves as a network of cross-linked chains characteristic of a gel phase, yet it is poised near the sol phase, a solution of independent chains. Chromosome organization near the phase boundary provides the genome with a tradeoff between stability and responsiveness and orchestrates the timing of genomic interactions. |
Thursday, March 5, 2020 11:51AM - 12:03PM |
S26.00002: A “Tug-of-War” in a three dimensional Double-Nanopore system Swarnadeep Seth, Aniket Bhattacharya In an experimental “Tug-of-War” (X. Liu et al., Small 2019, 1901704), a DNA segment co-captured in both the pores in a Double-Nanopore system is subject to two equal and opposite biases at two pore locations for better control and repeated measurements of the same segment. We simulate a model system in three dimensions and use Brownian dynamics to reveal the details of the single file translocation. Specifically, we study the consequence of increased persistence length of the segment in between the pores due to the tug-of-war forces. We characterize the diffusive motion of the chain either for exact “Tug-of-War” with zero bias, or subject to a small net bias, and provide error estimates of the length translocated through the Double- nanopore from the velocity measurements. Furthermore, we compare the velocities of the individual monomers with the average velocity of the entire chain and explore measures to reduce the fluctuation in velocity along the chain. |
Thursday, March 5, 2020 12:03PM - 12:15PM |
S26.00003: Studies of nucleosome-decorated DNA structures and deformations using a new analytical model Seyed Ahmad Sabok-Sayr, Wilma K Olson The two meters of DNA found in almost every human cell must be folded by many orders of magnitude to fit in the nucleus. The first step in this compaction involves the coiling of ~150 base pairs of DNA around a core of eight positively charged histone proteins. Understanding the biological processing of DNA requires knowledge of how the nucleosomes are arranged in space. We introduce a new analytical treatment of nucleosome-decorated DNA which is made up of three essential parts: nucleosomal DNA; protein-free stretches of DNA; and the intervening connectors. Every connector provides a physically smooth DNA pathway between a protein-bound and/or a protein-free segment. We have used this approach to study the energetically preferred configurations of torsionally relaxed, 360-base pair DNA rings with two evenly-spaced nucleosomes as well as rings of the same size with a single nucleosome subject to deformation in structure and/or variation in DNA wrapping. We have identified conditions where the closed DNA chain switches from one global configuration state to another. We are also using this model to study more complicated structures, such as the Simian virus 40 minichromosome, an assembly of ~20 nucleosomes on ~5200 base pairs of DNA supercoiling. |
Thursday, March 5, 2020 12:15PM - 12:27PM |
S26.00004: Long-lived memory and dynamics of liquefied chromatin Edward Banigan, Houda Belaghzal, Tyler Borrman, Job Dekker, Leonid Mirny Chromatin is organized into spatially segregated compartments, referred to as (active) euchromatin and (inactive) heterochromatin. Compartments are thought to be formed by phase separation, which may be facilitated by the underlying linear polymer structure of the genome. However, recent “liquid Hi-C” experiments in which chromosomes are fragmented into tiny segments reveal an hours-long spatial memory that does not rely on large-scale polymer connectivity. To understand the physical mechanisms and dynamics of this memory, we analyze Hi-C genome contact maps and perform polymer molecular dynamics simulations. In a heteropolymer simulation model, we find that strong interactions between inactive chromatin segments can lead to slow melting of inactive compartments, as in experiments. Surprisingly, in Hi-C maps, we find that contacts between segments separated by small genomic distances are maintained despite the fragmentation of the genome. Our model can only reproduce this counterintuitive behavior when such contacts are maintained by another cell nuclear structure, such as the lamina. Thus, while phase separation may globally compartmentalize chromatin, it is insufficient to dictate short-distance contacts, which instead may be maintained by specific, long-lived interactions. |
Thursday, March 5, 2020 12:27PM - 1:03PM |
S26.00005: The Dynamic Archaeal Chromatin “Slinky” Invited Speaker: Samuel Bowerman Eukaryotic organisms package genomes that are significantly larger and more complex than genomes that are typically found in prokaryotes. The fundamental unit of compaction is the nucleosome, which is formed by histone heteromers – two H2A-H2B dimers flanking an H3-H4 tetramer – forming an octamer that binds approximately 147 bp of DNA. While histones were originally thought to only be present in eukaryotes, a plethora of histone sequences have been identified in a wide range of archaea, one of the prokaryotic domains of life. Our lab recently determined the structure of histone-based archaeal chromatin that showed striking similarities to eukaryotic nucleosomes, but crystal lattice packing and biochemical experiments suggested that archaea may form repeated stacking interactions, potentially forming long “slinky-like” extended chromatin arrangements. Here, we utilize molecular dynamics simulations, cryoEM, and analytical ultracentrifugation to study the inherent dynamics of these putative chromatin slinkies. Formation of “slinky stacking” interactions are observed to reduce system dynamics, and perturbing this interaction through stack-hindering mutations yields more flexible constructs and increases solution accessibility. The openness of the slinky is also sensitive to the salt environment. We utilize these data to explore how inherent dynamics of archaeal slinky chromatin may regulate transcription. |
Thursday, March 5, 2020 1:03PM - 1:15PM |
S26.00006: 5-methyl-cytosine binding proteins loop DNA under nanoconfinement Ming Liu, David C. Williams, Hong Wang, Robert Riehn Methyl-binding domain proteins are a family of proteins that possess a domain to selectively bind 5-methyl cytosine in an CpG context. Members of the family interact with other proteins to modulate DNA packing. Stretching of DNA-protein complexes in nanofluidic channels with a cross-section of a few persistence lengths allows us to probe the degree of packing by such proteins. Herewe demonstrate compaction by MeCP2 while MBD2 does not affect DNA configuration. By using atomic force microscopy (AFM), we determined that the likely mechanism for compaction by MeCP2 is the formation of bridges between distant DNA stretches and the formation of loops. We discuss the potential of both proteins for epigenetic mapping. |
Thursday, March 5, 2020 1:15PM - 1:27PM |
S26.00007: Nuclear chromatin patterns: modeling dynamics of intra-chromatin interactions and its impact on structure organization Rabia Laghmach, Michele Di Pierro, Davit Potoyan The description of chromatin organization and its dynamics, at a large scale, are functionally important factors in the genome regulation function. Growing evidence suggests that chromatin within the nucleus has a liquid-like behavior mediated by phase separation into micro-droplets with distinct transcriptional states. The formation and spatial arrangement of chromatin droplets within the nucleus depending on their transcriptional states either active (euchromatin) or inactive (constitutive and facultative heterochromatin) genes are important features of the nuclear architecture. Understating mechanisms that control the dynamics and spatiotemporal regulation of droplets formation is a possible way to elucidate the relationship between nuclear architecture and gene regulation. Here, we introduce a mesoscale liquid model of nucleus (MELON) that incorporates dynamic of interactions between A-B-C chromatin compartments of the nucleus, as well as the affinity between constitutive heterochromatin and Lamina at the nuclear envelope and nucleus deformation. Using MELON framework, we show that phase separation together with surface tension effects and nuclear shape deformation is sufficient for recapitulating large-scale morphology and dynamics of chromatin along the life cycle of cells. |
Thursday, March 5, 2020 1:27PM - 1:39PM |
S26.00008: Long-distance group dynamics of RNA polymerases via DNA supercoiling Sangjin Kim Genes are often transcribed by multiple RNA polymerases (RNAPs) at densities that can vary widely across genes and environmental conditions. Here, we provide in vitro and in vivo evidence for a built-in mechanism by which co-transcribing RNAPs display either collaborative or antagonistic dynamics over long distances (>2 kb) through transcription-induced DNA supercoiling. In Escherichia coli, when the promoter is active, co-transcribing RNAPs translocate faster than a single RNAP, but their average speed is not altered by large variations in promoter strength and thus RNAP density. Environmentally induced promoter repression reduces the elongation efficiency of already-loaded RNAPs, causing premature termination and quick synthesis arrest of no-longer-needed proteins. This negative effect appears independent of RNAP convoy formation and is abrogated by topoisomerase I activity. Antagonistic dynamics can also occur between RNAPs from divergently transcribed gene pairs. Implications for genome organization and evolution will be discussed. Our findings may be broadly applicable given that transcription on topologically constrained DNA is the norm across organisms. |
Thursday, March 5, 2020 1:39PM - 1:51PM |
S26.00009: Interplay of chromatin self-adhesion and lengthwise compaction on interchromosomal organization Sumitabha Brahmachari, Vinicius Contessoto, Michele Di Pierro, Jose N Onuchic Chromosome folding is driven by an interplay between two major forces: self-adhesion between specific chromatin segments and lengthwise compaction, which is in line with experimental observations of structure and dynamics of cellular chromosomes. We use a coarse-grained polymer model for chromosomes where centromeres and telomeres are treated as polymer blocks featuring respective self-adhesion, and simulate multiple chromosomes in a confined volume. We find that our scheme of lengthwise compaction drives the formation of chromosome territories, whereas, self-adhesive centromeres and telomeres tend to form localized clusters. We highlight the interplay between self-adhesion and lengthwise compaction, based on their relative strengths, that addresses a fundamental aspect of genome organization in the eukaryotic nuclei. |
Thursday, March 5, 2020 1:51PM - 2:03PM |
S26.00010: A minimal model for correlated chromatin dynamics Kuang Liu, Alison Patteson, Edward Banigan, Jennifer Schwarz The multiscale spatial structure of chromatin spans several decades from the nanometer scale to the micron scale. In addition to its nontrivial spatial structure, chromatin also exhibits nontrivial dynamics. For instance, correlated motion of chromatin on the length scale of microns over the time scale of tens of seconds has been observed. Correlations are diminished in the absence of ATP, suggesting that motor/enzymatic activity promotes chromatin collective dynamics. Therefore, we construct a minimal polymeric model to study the spatiotemporal properties of chromatin by simulating a Rouse chain with excluded volume interactions confined within a rigid, spherical shell that represents the lamina. We characterize the spatiotemporal properties of the chain in the presence of motor activity, crosslinking, and binding to the shell. These components model an active chromatin network with lamin-binding domains. We find correlated motion under several conditions, without the need for long-range forces. Notably, when chromatin is bound to the lamina, crosslinking and motor activity are required for strong correlations in chromatin motion. We also study the effects of a deformable lamina shell in order to study the coupling of correlated chromatin motion to nuclear shape. |
Thursday, March 5, 2020 2:03PM - 2:15PM |
S26.00011: Synergistic Coordination of Chromatin Torsional Mechanics and Topoisomerase Activity Tung T Le, Xiang Gao, Seong ha Park, Jaeyoon Lee, James T. Inman, Joyce H Lee, Jessica L Killian, Ryan P Badman, James M Berger, Michelle D. Wang Due to the intrinsic twist of DNA, eukaryotic replication generates DNA supercoiling as the replisome unravels parental DNA. If not resolved, this supercoiling may intertwine chromatin fibers and result in significant topological challenges during chromosome replication. Since the replisome alone is incapable of driving its substrates out of torsional equilibrium, the generated supercoiling partitions ahead of or behind the replication fork to maintain a balance of torque. By making direct torque measurements, we demonstrated that a single chromatin fiber (as would be located ahead of a replisome) is torsionally soft, while a braided chromatin fiber (as would be located behind the replisome) is relatively stiff. These results imply that supercoiling on chromatin substrates is preferentially directed in front of the replication fork. We further showed that topoisomerase II relaxation displays a strong preference for a single chromatin fiber over a braided fiber, suggesting a synergistic coordination – the mechanical properties of chromatin inherently suppress intertwining during replication elongation by driving DNA supercoiling ahead of the fork, where it is more efficiently removed by topoisomerase II. This work highlights the fundamental role of physical principles in the cell. |
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