Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session E65: Physics of Genome Organization IFocus
|
Hide Abstracts |
Sponsoring Units: DBIO DPOLY GSNP Chair: Alexandre Morozov, Rutgers Univ Room: BCEC 260 |
Tuesday, March 5, 2019 8:00AM - 8:36AM |
E65.00001: Complexity in transcription factor – DNA recognition Invited Speaker: Martha Bulyk TBD |
Tuesday, March 5, 2019 8:36AM - 9:12AM |
E65.00002: Quantifying sequence readout by transcription factors through principled analysis of high-throughput SELEX data Invited Speaker: Hans Rube Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. In recent years, hundreds of TFs have been characterized using high-throughput in vitro DNA binding assays coupled with deep sequencing. Variations of these assays can characterize binding by TF complexes and by RNA-binding proteins, or binding to chemically modified DNA. However, no unified method for analyzing all these data yet exists. We recently developed an algorithm named No Read Left Behind or NRLB (Rastogi et al., PNAS, 2018), which infers biophysical binding specificity models across the full affinity range from single-round SELEX data. It predicts human MAX homodimer binding in near-perfect agreement with existing low-throughput measurements, captures the specificity of the full-length p53 tetramer, and distinguishes multiple binding modes within a single sample. In addition to the chemical identity of the DNA bases, TF binding affinity is sensitive to the local three-dimensional shape of the DNA double helix. We demonstrate that linear models based on mononucleotide features alone can account for 60–70% of the variance in the DNA shape parameters minor groove width, roll, helix twist, and propeller twist. We also show that NRLB binding models implicitly encode DNA shape readout. Building on these observations, we developed a post hoc analysis method that interprets NRLB models in terms of DNA shape readout (Rube et al., MSB, 2018). Finally, we will discuss our latest algorithm, ProBound, which, unlike NRLB, allows principled modeling of multiple SELEX rounds, chemically modified DNA, and complexes with variable spacing between the DNA binding domains. ProBound works on all currently available data and allows us to build a resource of DNA binding specificity models for hundreds of TFs. |
Tuesday, March 5, 2019 9:12AM - 9:24AM |
E65.00003: Heterodimer Transcription Factors as Novel Gene Regulators Kyle Naughton, James Boedicker Synthetic bacterial communities often incorporate quorum sensing (QS) networks to enable cell-cell communication. An intrinsic component of most QS networks is dimerization of receptor proteins around QS signals. Dimers of receptors act as transcription factors, modulating gene expression in the presence of high signal concentration. For example, LuxR binds a signal, forms a homodimer, and activates an operon in a feed-forward manner that makes more signal, more receptors, and invokes bioluminescence in Vibrio fisheri. In cells with more than one type of receptor protein, homodimers and heterodimers may form. The role of heterodimers and the conditions for their formation, however, remains murky. Some authors suggest heterodimers mute genes by competitively binding QS signals or forming inactive dimers. It remains possible, however, that heterodimer formation occurs in a purposeful way. We explore the possibility that heterodimers directly regulate gene expression based on experiments with tethered dimers. From a theoretical perspective use simple thermodynamic models to examine under what conditions heterodimers might form. Using MCMC and QS receptor position weight matrices we suggest DNA binding sites may exist which favor the heterodimers over either homodimer. |
Tuesday, March 5, 2019 9:24AM - 9:36AM |
E65.00004: Gene clustering drives co-regulation of disparate biological pathways in eukaryotes Richard Joh, Michael Lawrence, Martin Aryee, Mo Motamedi The establishment of distinct transcriptional states in response to developmental or environmental cues is critical for survival. This involves the concordant or discordant transcriptional regulation of several distinct biological pathways, often involving thousands of genes. How these system-level changes to transcriptomes are coordinated is an understudied problem in eukaryotic biology. Here, using computational and experimental approaches in eukaryotes ranging from yeast to human, we report that this coordination is in part achieved by the genic proximity of the regulatory nodes of disparate biological pathways whose co-regulation drives the transcriptional coherence of their respective pathways. Overall, our data identifies transcriptional co-regulation of hundreds of discreet biological pathways and suggest that genomic clustering of their transacting factors such as transcription factors create operon-like regulation in eukaryotes. |
Tuesday, March 5, 2019 9:36AM - 9:48AM |
E65.00005: Liquid-liquid phase separation driven organization of nuclear chromatin domains Rabia Laghmach, Davit Potoyan Chromatin of eukaryotic cells folds within few micrometers of nuclear space while still retaining dynamism and accessibility needed for function. Latest experiments have revealed a liquid like behavior of chromatin manifested in epigenetically mediated phase separation into micro-droplets with distinct transcriptional states. Motivated by these experiments we have devised a mesoscale liquid like model of nucleus (MELON) with chromatin states resolved as a viscoelastic fluid fields of type A and B corresponding to transcriptionally active and silent states. The model allows direct comparison with imaging experiments of different cell lines and during various stages in cell cycle. Using MELON framework, we investigate the roles of chromatin droplet diffusion, fluctuations and impact of phase separation kinetics on non-equilibrium processes of growth and inversion. We show that ideas based on classical theories of nucleation and phase separation can have a broad predictive power in capturing several salient features of intra-nuclear chromatin dynamics. |
Tuesday, March 5, 2019 9:48AM - 10:00AM |
E65.00006: Polymer Models of S. pombe Chromatin Peter Williams, Simon G Mochrie, Megan King, Corey Shane O'Hern Recent advances in Hi-C studies have laid the groundwork for understanding the organization of the genome at different points in the cell cycle. We present a coarse-grained polymer model with short-ranged attractions and volume exclusion that quantitatively recapitulates experimental Hi-C maps for the yeast strain, S. pombe. The polymer model gives rise to an ensemble of transient clusters corresponding to topologically associated domains. Insight on the dynamics of chromatin can be obtained from single particle tracking experiments on fluorescently tagged transgenic loci at strategic points in the genome. Transcription inhibitors have been shown to dramatically suppress the mean square displacements of the loci. These results imply that transcription is the source of activity within the nuclear envelope. We have also developed a coarse-grained model of polymerase translocating along a polymer. We model portions of the genome to identify the effect of activity on loci proximal and distal to regions of high gene expression. |
Tuesday, March 5, 2019 10:00AM - 10:12AM |
E65.00007: Bacterial chromosome organization: few special cross-links, cell confinement, and molecular crowders play the pivotal roles. Tejal Agarwal, Manjunath G. P., Farhat Habib, Apratim Chatterji Using a coarse-grained bead-spring model of bacterial chromosomes of C. crescentus and E. coli we show that just 33 and 38 effective cross-links in 4017 and 4642 monomer chain at special positions along the chain contour can lead to the large length-scale organization of the DNA polymer, where confinement effects of the cell walls play a crucial role in the organization. The positions of the 33/38 cross-links along the chain contour are chosen from the Hi-C contact map of bacteria C. crescentus and E. coli. We represent 1000 base pairs as a coarse-grained monomer in our bead-spring flexible ring polymer model of the DNA. Thus 4017/4642 beads on a flexible ring polymer represent the C. crescentus/ E. coli DNA polymer with ~4 million base pairs. Choosing suitable parameters from our preceding study, we also incorporate the role of molecular crowders and the ability of the chain to release topological constraints. We also validate our prediction of the organization of the bacterial chromosomes with available experimental data. |
Tuesday, March 5, 2019 10:12AM - 10:24AM |
E65.00008: Spatial proximity coordinates histone modification and expression of multiple genes Jingyu Zhang, Yan Zhang, Ivet Bahar, Jianhua Xing A cell type transition process requires temporally orchestrated global changes of gene expressions despite existence of large extrinsic and intrinsic stochasticity. One such major source of stochasticity is transcriptional bursting, where even under constant levels of trans-regulatory elements genes stochastically switch between a transcriptionally active and an inactive state. Such bursting dynamics may destroy temporal coordination of genes. We integrated datasets of gene expression, histone modification, and chromosome conformation for the mouse nervous system development and TGF-β treated MCF10A cells. We identified that genes having related functions and regulated by common TFs tend to cluster spatially and share similar histone modification patterns. Through a polymer-based model that describes cooperativity in histone modification dynamics, we predict that genes in proximity synchronize their transcriptions by synchronizing their stochastic switching between histone modification states with different transcriptional activities. This hypothesis is supported by analysis of allele-specific single cell RNAseq data, and we are further testing it with single cell FISH and superresolution imaging. |
Tuesday, March 5, 2019 10:24AM - 10:36AM |
E65.00009: Interphase chromatin as a self-returning random walk: Can DNA fold into liquid trees? Kai Huang, Vadim Backman, Igal G Szleifer We introduce a self-returning random walk to describe the structure of interphase chromatin. Based on a simple folding algorithm, our de novo model unifies the high contact frequency discovered by genomic techniques, and the high structural heterogeneity revealed by imaging techniques, which two chromatin properties we theoretically prove to be irreconcilable within a fractal polymer framework. Our model provides a holistic view of chromatin folding, in which the topologically associated domains are liquid-tree-like structures, linked and isolated by stretched out, transcriptionally active DNA to form a secondary structure of chromatin that further folds into a “3D forest” under confinement. The model pivots an unprecedentedly wide array of experimental observations and suggests the existence of a universal chromatin folding principle. Based on a global folding parameter, the model reveals a unique structure-function relation of chromatin, which is abnormal from a polymer point of view but explains some experimental observations of how chromatin responses to stress. |
Tuesday, March 5, 2019 10:36AM - 10:48AM |
E65.00010: Investigating dynamic chromatin states in a model cell organism Mary Lou Bailey, Jessica F Williams, Megan King, Simon G Mochrie Chromatin’s biological functions are inextricably linked to its spatial organization and real-time dynamics. I will describe research aimed at gaining new insight into chromatin organization and dynamics, focused on the emerging model of Topologically-Associated Domains (TADs) – 50-100 kb-length regions of the genome that show unusually high contact probability. To date, approaches capable of linking the physical TAD structure to chromatin dynamics have been lacking. I will present a novel data acquisition and analysis pipeline and preliminary results: We label specific gene loci within a model cell organism, S. pombe, with lacO arrays bound by fluorescent LacI-GFP proteins. We then image cell populations over time on a widefield microscope. These movies are used to track the motions of loci for large populations of single cells. Next, we analyze the diffusive behavior of the chromatin loci by determining the mean-square displacement and velocity autocorrelation function. To further investigate the underlying biology that contributes to locus motion, we compare perturbations to a variety of biological inputs, including temperature, the cytoskeleton, and proteins that are hypothesized to have key roles in TAD formation. |
Follow Us |
Engage
Become an APS Member |
My APS
Renew Membership |
Information for |
About APSThe American Physical Society (APS) is a non-profit membership organization working to advance the knowledge of physics. |
© 2024 American Physical Society
| All rights reserved | Terms of Use
| Contact Us
Headquarters
1 Physics Ellipse, College Park, MD 20740-3844
(301) 209-3200
Editorial Office
100 Motor Pkwy, Suite 110, Hauppauge, NY 11788
(631) 591-4000
Office of Public Affairs
529 14th St NW, Suite 1050, Washington, D.C. 20045-2001
(202) 662-8700