Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session S65: Physics of Genome Organization IIFocus
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Sponsoring Units: DBIO DPOLY GSNP Chair: Alexandre Morozov, Rutgers Univ Room: BCEC 260 |
Thursday, March 7, 2019 11:15AM - 11:51AM |
S65.00001: Measuring the energetics of transcriptional regulation in living cells using allelic manifolds Invited Speaker: Justin Kinney Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of "allelic manifolds", a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed DNA regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and σ70 RNA polymerase. Doing so, we consistently obtained energetic measurements precise to ~ 0.1 kcal/mol (equivalently, ~0.2 kBT). We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable. |
Thursday, March 7, 2019 11:51AM - 12:03PM |
S65.00002: The Influence of Nucleosome Energetics on Chromatin Structure Across Multiple Length-Scales Joshua Moller, Joshua Lequieu, Juan De Pablo The physics governing nucleosome interactions influence structural features of chromatin across a range of length-scales. Here, we assess the extent of these interactions through Brownian dynamics simulations using a recently-developed coarse-grained model of chromatin. Simulations are used to interpret the hierarchy of interactions in chromatin fibers by quantifying the energetics of small-fibers including di- and trinucleosomes and isolating the factors which facilitate condensed configurations. Among these factors, we consider the influences of DNA sequence, nucleosome repeat length, and inclusion of the H1 linker histone. These small-fiber results are then used to assess the structure of larger chromatin fibers, revealing that nucleosomes in larger fibers favor configurations related to those exhibited in the small-scale systems. Lastly, we show that the linker histone significantly shifts the energetic minima of smaller systems, which corresponds to similar configuration changes of the larger chromatin fiber structure. |
Thursday, March 7, 2019 12:03PM - 12:15PM |
S65.00003: Modeling the spreading of epigenetic marks at the Oct4 promoter Melinda Varga, William C. Aird, Erzsébet Ravasz Regan Epigenetic phenomena govern a wide range of processes in biological systems from cell differentiation to cancer. Genes are activated and inactivated by the presence and absence of various epigenetic marks ranging from histone methylation and acetylation to DNA methylation. Several computational models were developed to shed light on the bistability of the expressed protein, but they are mostly conceptual inventories of mechanisms required for a switch-like behavior of promoters, without an attempt to match experimental data. Here we introduce a computational model of the promoter region of the Oct4 gene, in which we incorporate the processes of histone acetylation, histone methylation and the spreading of silencing marks via the HP1 protein complex, and DNA methylation. We show that our model’s dynamics align well with experimental results measured at the Oct4 promoter of mouse embryonic stem cells and can be adapted to describe the behavior of various promoters. We expect our approach to offer an important predictive tool to probe the strength of the epigenetic barrier to turn on a silenced gene and to predict the dependence of this barrier on the spatial organization of CpG sites. |
Thursday, March 7, 2019 12:15PM - 12:27PM |
S65.00004: The role of activity from within and outside of the cell nucleus in nuclear blebbing Kuang Liu, Edward Banigan, Alison E. Patteson, J. M. Schwarz The cell nucleus is an active environment in which molecular motors such as RNA polymerase and condensin continuously remodel chromatin. Outside the nucleus, the cytoskeleton is an active semiflexible polymer network comprised of actin, microtubules, and intermediate filaments, with motors, such as myosin and kinesin, remodeling the network. These two active environments are mechanically coupled via LINC complexes embedded in the nuclear membranes, as well as direct steric interactions at their interface. We numerically study shape fluctuations at the interface of these two active environments. We focus on the formation of nuclear blebs, which are large bulges in the nuclear envelope that frequently occur in the cells of individuals with diseases, such as muscular dystrophy or progeria. In particular, we study how bleb formation depends on the type of activity in the nucleus, be it contractile or extensile, to explain such phenomena as nuclear blebs occurring more frequently for diseased cells in stiffer or more confined microenvironments than in softer ones. |
Thursday, March 7, 2019 12:27PM - 12:39PM |
S65.00005: Modeling intrinsic biases in high-throughput sequencing data for chromatin accessibility Shengen Hu, Chongzhi Zang Genome-wide profiling of chromatin accessibility with the assay for transposase-accessible chromatin using sequencing (ATAC-seq) or DNaseI hypersensitivity sequencing (DNase-seq) has been widely used for studying regulatory DNA elements and transcriptional regulation in many cellular systems. Efficient and thorough computational analysis is essential for extracting biological information from such high-throughput sequencing data. It has been reported that DNase cleavage of DNA has sequence preferences that can significantly affect the footprint patterns at transcription factor binding sites in genomic profiles. We found that enzymatic sequence biases commonly exist in both bulk and single-cell chromatin accessibility profiling data. Using a regular simplex encoding model, we developed a quantitative approach for accurate characterization and systematic correction of intrinsic sequence biases contained in ATAC-seq and DNase-seq data. This approach can be applied in bioinformatics for improved analysis of high-throughput chromatin accessibility sequencing. |
Thursday, March 7, 2019 12:39PM - 12:51PM |
S65.00006: WITHDRAWN ABSTRACT
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Thursday, March 7, 2019 12:51PM - 1:03PM |
S65.00007: The structural consequences of one-sided loop extrusion Edward Banigan, Aafke van den Berg, Hugo B Brandao, John Frederick Marko, Leonid Mirny SMC complexes, such as condensin or cohesin, organize chromatin in various scenarios across many cell types by a process known as loop extrusion. These complexes reel in DNA and extrude it as a loop in a directed and ATP-dependent manner. Recent in vitro experiments show that, in contrast to existing models, loop extrusion is “one-sided” so that SMC complexes reel in and extrude DNA from only one side. We develop theoretical and simulation models to determine whether one-sided extrusion can explain phenomena such as mitotic chromosome compaction, interphase TAD formation, and juxtaposition of bacterial chromosome arms. We find that purely one-sided extrusion cannot explain these phenomena, but simple variants in which extrusion becomes effectively two-sided can rescue chromosome morphology in these scenarios. Our results suggest that there must be factors in vivo that promote two-sided extrusion or other SMC complex cooperativity. |
Thursday, March 7, 2019 1:03PM - 1:15PM |
S65.00008: Noninvasive imaging of 3D dynamics in the cell nucleus Yoon Jung, Kuan-Chung Su, William H Bloxham, Iain M. Cheeseman, Nikta Fakhri The cell nucleus is a highly dynamic organelle which controls the activities of the cell by regulating gene expression. The complex dynamics of nuclear proteins span a large range of length and time scales which can be studied with fluorescence microscopy to understand how interactions at the molecular level lead to collective behavior. However, challenges remain as data acquisition is limited to short time scales due to fluorophore instability and photodamage by excitation light sources. We introduce an experimental technique using single-walled carbon nanotubes combined with near-infrared excitation to circumvent photodamage. Furthermore, we collect 3D trajectories of these fluorophores processed by novel reconstruction algorithms to understand behavior in crowded environments. This technique will serve as an effective tool to study the cell nucleus dynamics during different stages of the cell cycle. |
Thursday, March 7, 2019 1:15PM - 1:27PM |
S65.00009: Interplay of Loop Extrusion, Compartmentalization and Global Chromosome Dynamics Across Conditions and the Cell Cycle Johannes Nuebler, Geoffrey Fudenberg, Maxim Imakaev, Nezar Abdennur, Leonid Mirny The most widely known and most striking aspect of chromosome dynamics is their strong compaction for cell division. Thereafter, they are released into more extended conformations, and assume a high degree of spatial organization. Prominent examples are: (i) local interaction domains (TADs) due to active extrusion of chromatin loops, (ii) segregation of active and inactive sections into distinct spatial compartments, likely due to a phase separation process, and (iii) chromosome territoriality, i.e. a chromosomes spatial extent is far smaller than the corresponding equilibrium polymer coil. |
Thursday, March 7, 2019 1:27PM - 1:39PM |
S65.00010: A microscopic theory for chromosome congression in C. elegans mitotic spindle Ehssan Nazockdast, Michael John Shelley, Stephanie Redemann The accurate separation of chromosomes during cell division is key to survival and proper development. As the nuclear envelope breaks down, the microtubules within the spindle begin to interact with chromosomes. The disordered chromosomes, then, congress and are aligned in the mid-plane of the bipolar spindle. The underlying active forces that move the chromosomes during this process are poorly understood. We utilize the data from the first full 3D tomographic reconstructions of C. elegans mitotic spindle to understand how individual microtubules interact with chromosomes and propose a microscopic theory for chromosome congression. In addition to predicting the observed length distribution of microtubules in tomography, our theory correctly predicts a mechanically stable half spindle structure, as is observed in cells with monopolar spindles. Most remarkably, we find that the shapes (curvature) of microtubules based on our micromechanical theory are in good agreement with the tomography results. |
Thursday, March 7, 2019 1:39PM - 1:51PM |
S65.00011: Optimizing chromosome disentanglement via chromatin loop organization Sumitabha Brahmachari, John Frederick Marko Chromosome structure is actively regulated by a concerted action of various proteins to avail vital cellular functions, like the mitotic segregation of chromosomes. We seek to understand the microscopic scheme underlying the structure manipulation that leads to a compact disentangled mitotic state from a less compact and more entangled state in interphase, and vice-versa. We model cellular chromosomes as polymer brushes in a confined volume, and calculate the level of inter-chromosome entanglement in a fluctuating-topology ensemble for various steady-state configurations defined by structural parameters like the grafting density and side chain or loop length. We find that entanglements are minimized for certain brush configurations that depend on net chromosome length. Comparing with existing experimental observations we suggest that chromosomal loops are important for maintaining a low level of entanglement during the cell cycle. Our model provides a steady-state description of chromosomes that is consistent with experimental observations for both the interphase and mitotic stages, where the cell-cycle-specific reorganizations in the structure are accounted for by evolution of the steady state, likely driven by loop extrusion. |
Thursday, March 7, 2019 1:51PM - 2:03PM |
S65.00012: Modulation of the DNA accessibility in the nucleosome -- insights from basic physics. Alexey Onufriev The nucleosome, a complex of 147 base-pairs of DNA with eight histone proteins, must protect its DNA, but, at the same time, allow on-demand access to it when needed by the cell. The exact mechanism of the control remain unclear. |
Thursday, March 7, 2019 2:03PM - 2:15PM |
S65.00013: How nucleoid associated proteins stabilize supercoiled DNA Katelyn Dahlke, Charles E. Sing Nucleoid associated proteins (NAPs) play an important physical role in prokaryotic cells by manipulating the shape and structure of the DNA within the nucleoid. These NAPs bend or twist DNA, and there are indications that NAPs bind preferentially to DNA that is already locally deformed. We hypothesize that these binding behaviors and local deformations strongly impact the stability and structure of DNA. |
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