Bulletin of the American Physical Society
APS March Meeting 2023
Volume 68, Number 3
Las Vegas, Nevada (March 5-10)
Virtual (March 20-22); Time Zone: Pacific Time
Session S08: Genome Organization and Subnuclear Phenomena II: Active and Passive Processes in Genome OrganizationFocus
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Sponsoring Units: DBIO Chair: Jan Spille, University of Illinois Chicago Room: Room 131 |
Thursday, March 9, 2023 8:00AM - 8:36AM |
S08.00001: Structural changes in chromosomes driven by multiple condensin motors during mitosis Invited Speaker: Devarajan Thirumalai We created a theoretical framework that describes the loop extrusion (LE) by multiple condensin I and II motors in order to investigate the changes in chromosome organization during mitosis. The theory accurately reproduces the experimentally measured contact probability profiles for the mitotic chromosomes in HeLa and DT40 cells without any parameters. The rate of loop extrusion is smaller at the start of mitosis and increases as the cells approach the metaphase. The mean loop size generated by condensin II is about six times larger than the ones created by condensin I. The loops, which overlap with each other, are stapled to a central dynamically changing helical scaffold formed by the motors during the LE process. The structures of the mitotic chromosomes, using a data-driven method that uses the Hi-C contact map as input, are best described as random helix perversion (RHP) in which the handedness changes randomly along the scaffold. The extent of propagation in the RHP structures is less in HeLa cells than in the DT40 chromosomes. |
Thursday, March 9, 2023 8:36AM - 8:48AM |
S08.00002: Theory of chromatin organization maintained by active loop extrusion Brian Chan, Michael Rubinstein The active loop extrusion hypothesis proposes that chromatin threads through the cohesin protein complex into progressively larger loops until reaching specific boundary elements. We build upon this hypothesis and develop an analytical theory for active loop extrusion which predicts that loop formation probability is a non-monotonic function of loop length and describes chromatin contact probabilities. We validate our model with Monte Carlo and hybrid Molecular Dynamics – Monte Carlo simulations and demonstrate that our theory recapitulates experimental chromatin conformation capture data. Our results support active loop extrusion as a mechanism for chromatin organization and provide an analytical description of chromatin organization that may be used to specifically modify chromatin contact probabilities. |
Thursday, March 9, 2023 8:48AM - 9:00AM |
S08.00003: Inferring chromatin loop configurations via a loop extrusion factor (LEF) model based on measured LEF density Tianyu Yuan, Tianyu Yuan, Hao Yan, Mary Lou P Bailey, Jessica F Williams, Ivan Surovtsev, Megan C King, Simon G Mochrie Chromosome conformation capture (Hi-C) quantifies chromatin organization via “contact maps” that represent the relative probability of two genomic loci to be proximal. Hi-C maps have led to the identification of topologically associating domains (TADs) as key elements of the mesoscale chromatin organization. In turn, the loop extrusion factor (LEF) model has emerged as the preferred mechanism underlying TAD formation. In this model, each LEF — e.g. the DNA-binding ATPase, cohesin — binds to chromatin and initiates loop extrusion, which proceeds until the LEF dissociates or is blocked by another LEF or by a “boundary element” (BE). BE locations and activities are critical for establishing TAD patterns, and, although some BEs have been identified, many questions concerning BE identity and activity remain, thus frustrating comparisons between Hi-C data and simulations. To bypass this knowledge deficit, we reasoned that it may be possible to use the cohesin ChIP-seq data as a proxy for LEF-BE interactions. Accordingly, we present modified LEF model simulation in which the position-dependent loop extrusion rate follows directly from cohesin ChIP-seq data. For several genomic regions of several organisms, we compare (1) the simulated LEF density to cohesin ChIP-seq data, and (2) simulated and experimental Hi-C maps. This approach has the potential to accurately characterize the dynamic loop configuration of any desired genomic region in any organism. |
Thursday, March 9, 2023 9:00AM - 9:12AM |
S08.00004: The little condensins that could: How tiny condensins move colossal chromosomes Atreya Dey During cell division hundreds of thousands of 5nm long condensin molecules come together to fold the micrometer long chromosomes by loop extrusion. However, experimental data is available either at the 5nm scale (as single molecule experiments) or at the micron scale (as Hi-C). Thus, we built a kinetic model of multiple condensins that can bridge this gap in length scales. The loops from the kinetic model are used as a scaffold in a generalized rouse model to create chromosome structures. We call this an Active Generalized Rouse Model for chromosomes (A-GRMC). The A-GRMC model can accurately reproduce the experimentally measured contact probability profiles in HeLa and DT40 cells without any parameter fit. We show that complex loop architectures such as Z-loops or nested loops arise in the mitotic chromosomes. These loops are stapled to a dynamically changing backbone formed by the motors. The model also lets us predict that loop extrusion speeds up as mitosis progresses. This work is the first theoretical study of mitotic chromosomes with active loop extrusion. |
Thursday, March 9, 2023 9:12AM - 9:24AM |
S08.00005: Transcription is a moving barrier to loop extrusion that shapes the genome Edward J Banigan, Wen Tang, Aafke van den Berg, Roman Stocsits, Gordana Wutz, Hugo Brandão, Georg Busslinger, Jan-Michael Peters, Leonid A Mirny The protein complex cohesin folds chromosomes by "loop extrusion," through which it extrudes the chromatin fiber into loops. Through interactions with stationary boundary elements, such as CTCF proteins, extrusion generates characteristic patterns of genomic contacts and chromatin spatial organization. Actively translocating elements, such as transcribing RNA polymerase motors, may also act as boundaries, but it has not been established how mobile boundaries might generate spatial genomic patterns. We analyzed chromosome conformation capture (Hi-C) data near active and inactive genes under conditions with normal or altered cohesin dynamics. Based on new observed patterns of genome organization, we developed a "moving barrier" model for transcription-extrusion interactions, in which polymerases impede and push loop-extruding cohesins. We developed a theoretical model to explain how cohesin accumulation results from different cohesin behaviors in the presence of polymerase. The model provides quantitative predictions for the effective boundary strength of active genes, the asymmetry in the boundary, and the dependence of these quantities on gene length. Our analysis demonstrates how the activity of loop-extruding motors can be modulated by other active, mobile elements to spatially organize the genome. |
Thursday, March 9, 2023 9:24AM - 9:36AM |
S08.00006: Active Transcription Regulates Mesoscale Genomic Organization via Active Extrusion of Chromatin Loops Aayush Kant, Zixian Guo, Vivek b Shenoy Transcriptional activity has recently been shown to increase the DNA supercoiling accelerating the formation of transcriptionally active DNA loops, and hence potentially dictating chromatin spatial organization. However, the quantitative role that transcription and epigenetic regulation synergistically play in genome-wide chromatin organization is yet unknown. We present a mesoscale phase-field model to explain the underlying physics of nuclear chromatin organization in presence of DNA looping. We capture the chromatin-lamina and chromatin self-interaction energetics and the kinetics of the diffusion of nucleoplasm and epigenetic marks. In addition, methylation and acetylation reactions drive a non-conservative interconversion of the euchromatin (EC) and heterochromatin (HC) phases. DNA loop extrusion is captured via a kinetic conversion of HC into EC in RNAPII-rich regions. Our analysis predicts that at steady state HC domain size is governed solely by the kinetics of acetylation, methylation, and DNA loop extrusion. Our simulations, with super-resolution H2B imaging of in-vitro nuclei, reveal that the transcription abrogation increases HC domain sizes. We predict that enhanced DNA looping results in smaller HC domains – validated by super-resolution imaging of WAPL-deficient nuclei. Lastly, we predict the joint effects of WAPL deficiency and transcription such that chromatin decompaction in WAPL-deficient nuclei is blocked by inhibiting transcription. By uncovering the physical mechanisms of mesoscale chromatin organization in the nucleus, our model presents a new step in understanding how cell fate is affected by its chemo-mechanical environment. |
Thursday, March 9, 2023 9:36AM - 9:48AM |
S08.00007: Chromatin compartments from correlated active processes Deepti Kannan, Andriy Goychuk, Mehran Kardar, Arup K Chakraborty Gene transcription and its regulation involve active, energy-consuming processes, which induce correlated motion and enhance the subdiffusion of chromosomal loci. However, our current understanding of chromatin folding is largely based on equilibrium theories. To address this gap, we study a model of an active polymer driven by correlated active forces with non-uniform magnitude. Our analysis shows that active regions of the polymer bend and expand, while inactive regions straighten out and condense, resembling the morphology of heterochromatin (B) and euchromatin (A). Using polymer simulations, we predict that modest activity differences are sufficient to recapitulate the degree of AB compartmentalization observed in chromosome conformation capture (3C) experiments. Moreover, we find that distinct loci experiencing correlated active forces will effectively attract as if coupled by harmonic springs, while anticorrelations lead to repulsion. Thus, our theory offers non-equilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. Collectively, our work provides new avenues for the interpretation of data on chromosomes, and has broad implications for active polymer systems. |
Thursday, March 9, 2023 9:48AM - 10:00AM |
S08.00008: Organizational principles of active chromatin at transcription condensates Jan-Hendrik Spille, Ganesh Pandey, Alisha Budhathoki, Filmon Medhanie Many biomolecular condensates associate with specific chromatin loci in the cell nucleus. Transcription condensates are linked to super-enhancer chromatin domains that are characterized by extended accumulations of transcription factor and coactivator binding sites as well as stereotypic epigenetic marks. Bulk assays suggest that these chromatin marks are required to maintain transcription condensates at specific chromatin loci. We use multi-color super-resolution microscopy to investigate the spatial organization of chromatin and transcription condensates. Our results indicate an enrichment of active chromatin at the condensate surface. We discuss implications for the mechanical interaction between condensates and chromatin as well as structure-function relationships of transcription condensates. |
Thursday, March 9, 2023 10:00AM - 10:12AM |
S08.00009: Three-dimensional multiphase liquid chromatin model of eukaryotic nucleus Rabia Laghmach, Michele Di Pierro, Davit Potoyan The interior of the eukaryotic cell nucleus has a crowded and heterogeneous environment packed with chromatin polymers, regulatory proteins, and RNA molecules. Chromatin polymer, assisted by epigenetic modifications, protein and RNA binders, forms multi-scale compartments which help regulate genes in response to cellular signals. Furthermore, chromatin compartments are dynamic and tend to evolve in size and composition in ways that are not fully understood. To understand and disentangle the complex interplay of forces that contribute to the emergent patterns of chromatin organization and dynamics, we have devised a phenomenological field-theoretic model of the nucleus as a multiphase condensate of liquid chromatin types. Armed with the developed 3D mesoscopic model of nuclear chromatin, we have shed light on the distinct dynamical and structural contributions of chromatin-type interactions, the intermingling of chromosomal territories, and lamina binding. We also shed light on the dynamical heterogeneity and coherent motions of chromatin domains which are fully captured by an interplay of micro-phase separation of chromatin types and lamina binding. |
Thursday, March 9, 2023 10:12AM - 10:24AM |
S08.00010: Condensation dynamics of sticky chromatin Adam R Lamson, Olga Troyanskaya, Michael J Shelley Multicellular organisms require cells to differentiate to perform specific tasks and functions even though every cell contains the information necessary to produce all cell types of that organism. Cells differentiate by regulating gene expression in various ways. One way is by forming DNA-protein condensates inside the nucleus. Certain condensates, such as heterochromatin, suppress gene expression while others, like transcription hubs, up-regulate gene expression in the surrounding nuclear region. Current biomolecular condensate models explain equilibrium properties, like size and stability, but lack dynamics. For example, rheological properties and collapse times for large lengths of chromatin remain poorly characterized or explained. To study such dynamics, we use a mixture of coarse-grained 3D Brownian dynamics and kinetic Monte-Carlo algorithms to model DNA and associated binding proteins. Our simulations reveal two ways 'sticky' filaments go from being uncondensed, to condensed at multiple locations, to having a single condensate populating the filament. The conformational path taken is determined by the protein-DNA binding kinetics, the protein density, and the filament slack. This work sheds light on DNA and chromatin fibers reorganization on time-scales physically relevant to the cell cycle and crucial for proper gene expression during events like cell division. |
Thursday, March 9, 2023 10:24AM - 10:36AM |
S08.00011: Intermolecular interaction and local chromatin density regulate biomolecular condensate growth inside the nucleus Deb S Banerjee, Tafadzwa Chigumira, Josiah Kratz, David M Chenoweth, Shiladitya Banerjee, Huaiying Zhang Biomolecular condensates play important functional roles in many cellular processes. How the complex mechanical environment of the cell affects the growth of biomolecular condensates is not well understood. We study the growth of biomolecular condensates embedded in the chromatin network inside the nucleus. Chemical dimerization tools were used to induce protein condensates and their growth dynamics was observed for many hours. We combine theoretical modelling and experiments to characterize the growth dynamics of the condensates (droplets). We uncover the criteria for ripening-suppressed droplet growth and growth via ripening, depending on local chromatin stiffness, and demonstrate that these two distinct droplet dynamics may coexist within the complex mechanical environment inside the nucleus. Our theoretical predictions and experimental quantifications show that depending on the properties of the droplet forming protein and the mechanical properties of the chromatin network, the droplets can be stable or undergo ripening. Our overall findings point towards a possible repertoire of control mechanisms the cell can employ to regulate many aspects of the biomolecular condensate growth dynamics inside the nucleus. |
Thursday, March 9, 2023 10:36AM - 10:48AM |
S08.00012: Multiscale modeling of chromatin condensates Andrew Golembeski, Joshua Lequieu Recent experiments suggest that phase separation plays a role in the organization of chromatin yet the underlying molecular mechanisms remain unclear. Our work presents a molecular view of chromatin condensates using a multiscale model of chromatin. This multiscale model is efficient enough to access the large length scales of phase separation yet retains chemical details such as post-translational modifications. Our model reproduces recent experiments with phase-separated chromatin fibers and provides molecular information of chromatin condensates at nucleosome resolution. With this information we quantified the effects of histone acetylation on condensate stability and characterized the condensate's chromatin fiber structure. Our results demonstrate that short chromatin fibers form liquid-like condensates. Our results also suggest that chromatin fibers are dynamic and irregularly folded within condensed chromatin and do not contain signatures of a 30-nm chromatin fiber. Lastly we show that chromatin condensates can be disrupted by weakening specific nucleosome-nucleosome orientations and how certain histone-modifications can drive the reorganization of chromatin. |
Thursday, March 9, 2023 10:48AM - 11:00AM |
S08.00013: Multivalent binding proteins can drive collapse and reswelling of chromatin in confinement Sougata Guha, Mithun K Mitra Collapsed conformations of chromatin have been long suspected of being mediated by interactions with multivalent binding proteins, which can bring together distant sections of the chromatin fiber. In this study, we use Langevin dynamics simulation of a coarse grained chromatin polymer to show that the role of binding proteins can be more nuanced than previously suspected. In particular, for chromatin polymer in confinement, entropic forces can drive reswelling of collapsed chromatin with increasing binder concentrations, and this reswelling transition happens at physiologically relevant binder concentrations. Both the extent of collapse, and also of reswelling depends on the strength of confinement. We also study the kinetics of collapse and reswelling and show that both processes occur in similar timescales. We characterise this reswelling of chromatin in biologically relevant regimes and discuss the non-trivial role of multivalent binding proteins in mediating the spatial organisation of the genome. |
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