Bulletin of the American Physical Society
APS March Meeting 2017
Volume 62, Number 4
Monday–Friday, March 13–17, 2017; New Orleans, Louisiana
Session F4: Physics of Genome Organization: from DNA to Chromatin IFocus
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Sponsoring Units: DBIO GSNP Chair: Alexandre Morozov, Rutgers University Room: 263 |
Tuesday, March 14, 2017 11:15AM - 11:51AM |
F4.00001: Escherichia coli chromosomal loci segregate from midcell with universal dynamics Invited Speaker: Paul Wiggins The structure of the \textit{Escherichia coli} chromosome is inherently dynamic over the duration of the cell cycle. Genetic loci undergo both stochastic motion around their initial positions and directed motion to opposite poles of the rod-shaped cell during segregation. We developed a quantitative method to characterize cell-cycle dynamics of the \textit{E.\,coli} chromosome in order to probe the chromosomal steady state mobility and segregation process. By tracking fluorescently-labeled chromosomal loci in thousands of cells throughout the entire cell cycle, our method allows for the statistical analysis of locus position and motion, the step-size distribution for movement during segregation, and the locus drift velocity. The robust statistics of our detailed analysis of the wildtype \textit{E.\,coli} nucleoid allow us to observe loci moving toward midcell prior to segregation, consistent with a replication factory model. Then as segregation initiates, we perform a detailed characterization of the average segregation velocity of loci. Contrary to origin-centric models of segregation, which predict distinct dynamics for \textit{oriC}-proximal versus \textit{oriC}-distal loci, we find that the dynamics of loci were universal and independent of genetic position. [Preview Abstract] |
Tuesday, March 14, 2017 11:51AM - 12:03PM |
F4.00002: De~Novo~Chromosome Structure Prediction Michele Di Pierro, Ryan R. Cheng, Erez Lieberman-Aiden, Peter G. Wolynes, Jose' N. Onuchic Chromatin consists of DNA and hundreds of proteins that interact with the genetic material. \textit{In vivo}, chromatin folds into nonrandom structures. The physical mechanism leading to these characteristic conformations, however, remains poorly understood. We recently introduced MiChroM [1], a model that generates chromosome conformations by using the idea that chromatin can be subdivided into types based on its biochemical interactions. Here we extend and complete our previous finding by showing that structural chromatin types can be inferred from ChIP-Seq data. Chromatin types, which are distinct from DNA sequence, are partially epigenetically controlled and change during cell differentiation, thus constituting a link between epigenetics, chromosomal organization, and cell development. We show that, for~GM12878 lymphoblastoid cells~we are able to predict accurate chromosome structures with the only input of genomic data.~The degree of accuracy achieved by our prediction supports the viability of the proposed physical mechanism of chromatin folding and makes the computational model a powerful tool for future investigations. [1] M. Di Pierro, \textit{et al.} ; Transferable model for chromosome architecture; PNAS 2016 113 (43) 12168-12173 [Preview Abstract] |
Tuesday, March 14, 2017 12:03PM - 12:15PM |
F4.00003: Chromosomal Organization by an Interplay of Loop Extrusion and Compartment Interaction Johannes Nuebler, Geoffrey Fudenberg, Maxim Imakaev, Carolyn Lu, Anton Goloborodko, Nezar Abdennur, Leonid Mirny The chromatin fiber in eukaryotic nuclei is far from being simply a confined but otherwise randomly arranged polymer. Rather, it shows a high degree of spatial organization on all length scales, from individual nucleosomes up to well-segregated chromosome territories. On intermediate scales, chromosome conformation capture techniques have revealed two ubiquitous modes of organization: an alternating structure of A/B compartments, where each type preferentially associates with other base pairs of its type, and, typically on a smaller scale, the formation of topologically associating domains (TADs) with increased association within each domain but not across boundaries. The mechanisms behind this organization are only beginning to emerge. We review how the model of active loop extrusion can explain in a unified way such diverse phenomena as TAD formation and mitotic compaction and segregation, and we address in particular to what extent the interplay of active loop extrusion and compartment structure is compatible with recent experiments that interfere with the loading of the proposed loop extrusion factor cohesin. [Preview Abstract] |
Tuesday, March 14, 2017 12:15PM - 12:27PM |
F4.00004: Elucidating the role of transcription in shaping the 3D structure of the bacterial genome Hugo B. Brandao, Xindan Wang, David Z. Rudner, Leonid Mirny Active transcription has been linked to several genome conformation changes in bacteria, including the recruitment of chromosomal DNA to the cell membrane and formation of nucleoid clusters. Using genomic and imaging data as input into mathematical models and polymer simulations, we sought to explore the extent to which bacterial 3D genome structure could be explained by 1D transcription tracks. Using B. subtilis as a model organism, we investigated via polymer simulations the role of loop extrusion and DNA super-coiling on the formation of interaction domains and other fine-scale features that are visible in chromosome conformation capture (Hi-C) data. We then explored the role of the condensin structural maintenance of chromosome complex on the alignment of chromosomal arms. A parameter-free transcription traffic model demonstrated that mean chromosomal arm alignment can be quantitatively explained, and the effects on arm alignment in genomically rearranged strains of B. subtilis were accurately predicted. [Preview Abstract] |
Tuesday, March 14, 2017 12:27PM - 12:39PM |
F4.00005: A Minimal Polymer Model Integrates an Inverted Nuclear Geometry with Conventional Hi-C Compartmentalization Martin Falk, Natasha Naumova, Geoffrey Fudenberg, Yana Feodorova, Maxim Imakaev, Job Dekker, Irina Solovei, Leonid Mirny The organization of interphase nuclei differs dramatically across cell types in a functionally-relevant fashion. A striking example is found in the rod photoreceptors of nocturnal mammals, where the conventional nuclear organization is inverted. In particular, in murine rods, constitutive heterochromatin is packed into a single chromocenter in the nuclear center, which is encircled by a shell of facultative heterochromatin and then by an outermost shell of euchromatin. Surprisingly, Hi-C maps of conventional and inverted nuclei display remarkably similar compartmentalization between heterochromatin and euchromatin.~Here, we simulate a~\textit{de novo}~polymer model that is capable of replicating both conventional and inverted geometries~while preserving the patterns of compartmentalization as observed by Hi-C. In this model, chromatin is a polymer composed of three classes of monomers arranged in blocks representing constitutive heterochromatin, facultative heterochromatin, and euchromatin. Different classes of monomers have different levels of attraction to each other and to the nuclear lamina. Our results indicate that preferential interactions between facultative heterochromatin and constitutive heterochromatin provide a possible mechanism to explain nuclear inversion when association with the lamina is lost. [Preview Abstract] |
Tuesday, March 14, 2017 12:39PM - 12:51PM |
F4.00006: A maximum entropy model for chromatin structure Pau Farre, Eldon Emberly The DNA inside the nucleus of eukaryotic cells shows a variety of conserved structures at different length scales These structures are formed by interactions between protein complexes that bind to the DNA and regulate gene activity. Recent high throughput sequencing techniques allow for the measurement both of the genome wide contact map of the folded DNA within a cell (HiC) and where various proteins are bound to the DNA (ChIP-seq). In this talk I will present a maximum-entropy method capable of both predicting HiC contact maps from binding data, and binding data from HiC contact maps. This method results in an intuitive Ising-type model that is able to predict how altering the presence of binding factors can modify chromosome conformation, without the need of polymer simulations. [Preview Abstract] |
Tuesday, March 14, 2017 12:51PM - 1:27PM |
F4.00007: The "self-stirred" genome: Bulk and surface dynamics of the~chromatin globule Invited Speaker: Alexandra Zidovska Chromatin structure and dynamics control all aspects of DNA biology yet are poorly understood. In interphase, time between two cell divisions, chromatin fills the cell nucleus in its minimally condensed polymeric state. Chromatin serves as substrate to a number of biological processes, e.g. gene expression and DNA replication, which require it to become locally restructured. These are energy-consuming processes giving rise to non-equilibrium dynamics. Chromatin dynamics has been traditionally studied by imaging of fluorescently labeled nuclear proteins and single DNA-sites, thus focusing only on a small number of tracer particles. Recently, we developed an approach, displacement correlation spectroscopy (DCS) based on time-resolved image correlation analysis, to map chromatin dynamics simultaneously across the whole nucleus in cultured human cells [1]. DCS revealed that chromatin movement was coherent across large regions (4--5$\mu $m) for several seconds. Regions of coherent motion extended beyond the boundaries of single-chromosome territories, suggesting elastic coupling of motion over length scales much larger than those of genes [1]. These large-scale, coupled motions were ATP-dependent and unidirectional for several seconds. Following these observations, we developed a hydrodynamic theory of active chromatin dynamics, using the two-fluid model and describing the content of cell nucleus as a chromatin solution, which is subject to both passive thermal fluctuations and active (ATP-consuming) scalar and vector events [2]. In this work we continue in our efforts to elucidate the mechanism and function of the chromatin dynamics in interphase. We investigate the chromatin interactions with the nuclear envelope and compare the surface dynamics of the chromatin globule with its bulk dynamics. [1] Zidovska A, Weitz DA, Mitchison TJ, \textit{PNAS,~}110 (39), 15555, 2013 [2] Bruinsma R, Grosberg AY, Rabin Y, Zidovska A, \textit{Biophys. J.,}~106 (9), 1871, 2014 [Preview Abstract] |
Tuesday, March 14, 2017 1:27PM - 1:39PM |
F4.00008: New insights into nucleosome positioning and spacing Razvan Chereji, Srinivas Ramachandran, Steven Henikoff The basic units of DNA packaging are called nucleosomes – 147 bp of DNA wrapped around a histone octamer. Their locations on the chromosomes play an essential role in gene regulation. We use a novel technique of mapping nucleosomes, which virtually eliminates the background noise that is characteristic of nucleosome maps generated by other methods. We present a new method of obtaining precise measurements of inter-nucleosomal spacing at the single gene level, which confirms the linker “quantization” hypothesis. We show that statistical mechanics can predict the genome-wide nucleosome organization in yeast. References: [1] RV Chereji et al., Phys. Rev. E 83, 050903 (2011) [2] RV Chereji and AV Morozov, J. Stat. Phys. 144, 379 (2011) [3] RV Chereji and AV Morozov, Proc. Natl. Acad. Sci. U.S.A. 111, 5236 (2014) [4] D Ganguli et al., Genome Res. 24, 1637 (2014) [5] N Elfving et al., Nucleic Acids Res. 42, 5468 (2014) [6] HA Cole et al., Nucleic Acids Res. 42, 12512 (2014) [7] RV Chereji and AV Morozov, Brief. Funct. Genomics 14, 50 (2015) [8] RV Chereji et al., Nucleic Acids Res. 44, 1036 (2016) [9] J Ocampo et al., Nucleic Acids Res. 44, 4625 (2016) [10] H Qiu et al., Genome Res. 26, 211 (2016) [11] RV Chereji, S Ramachandran, S Henikoff, in preparation [Preview Abstract] |
Tuesday, March 14, 2017 1:39PM - 1:51PM |
F4.00009: Exploring the Interplay between DNA Sequence, Histone Tails and Nucleosome Dynamics Joshua Lequieu, Andres Cordoba, Juan de Pablo The dynamics of individual nucleosomes are influenced by both the underlying DNA sequence, as well as remodeling proteins that actively reposition nucleosomes along the genome. These remodeler proteins extract positioning information from the histones themselves, where certain histone modifications facilitate the remodeling of nearby chromatin regions. Recent work suggests that both of these processes occur simultaneously, with both DNA sequence and histone modifications thought to play different but complementary roles, yet the details of these processes are still poorly understood. In this work, we examine the interplay between DNA sequence and histone modifications using a detailed molecular model of the nucleosome. We demonstrate that DNA sequence plays an important role in the dynamics of nucleosome repositioning and that different DNA sequences reposition via different mechanisms. We then show that certain histone tails play important roles in this process by stabilizing metastable states, thereby encouraging specific rearrangements within the nucleosome and not others. Curiously, these histone tails are the same ones known to recruit remodeler proteins, suggesting a mechanism by which DNA sequence, histone tails and chromatin remodeling are coupled. [Preview Abstract] |
Tuesday, March 14, 2017 1:51PM - 2:03PM |
F4.00010: Mechanical properties of transription Stuart Sevier, Herbert Levine Over the last several decades it has been increasingly recognized~that both stochastic and mechanical processes play a central role in transcription. Though many aspects have been explained a number of fundamental properties are undeveloped.~ Recent results have pointed to mechanical feedback as the source of transcriptional bursting and DNA supercoiling but a reconciliation of this perspective with preexisting views of transcriptional is lacking. In this work we present a simple model of transcription where RNA elongation, RNA polymerase rotation and DNA supercoiling are coupled.~ The mechanical properties of each object form a foundational framework for understanding the physical nature of transcription. The resulting model can explain several important aspects of chromatin structure and generates a number of predictions for the mechanical properties of transcription. [Preview Abstract] |
Tuesday, March 14, 2017 2:03PM - 2:15PM |
F4.00011: Spatial organization of chromatin domains and compartments in single chromosomes Siyuan Wang, Jun-Han Su, Brian Beliveau, Bogdan Bintu, Jeffrey Moffitt, Chao-ting Wu, Xiaowei Zhuang The spatial organization of chromatin critically affects genome function. Recent chromosome-conformation-capture studies have revealed topologically associating domains (TADs) as a conserved feature of chromatin organization, but how TADs are spatially organized in individual chromosomes remains unknown. Here, we developed an imaging method for mapping the spatial positions of numerous genomic regions along individual chromosomes and traced the positions of TADs in human interphase autosomes and X chromosomes. We observed that chromosome folding deviates from the ideal fractal-globule model at large length scales and that TADs are largely organized into two compartments spatially arranged in a polarized manner in individual chromosomes. Active and inactive X chromosomes adopt different folding and compartmentalization configurations. These results suggest that the spatial organization of chromatin domains can change in response to regulation. [Preview Abstract] |
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