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1. Exploring chromosomal structural heterogeneity across multiple cell lines

   https://doi.org/10.7554/eLife.60312  

   Cheng, Ryan R; Contessoto, Vinicius G; Lieberman Aiden, Erez; Wolynes, Peter G; Di Pierro, Michele; Onuchic, Jose N (October 2020, eLife)

   null (Ed.)

   Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make two-state transitions between closed conformations and open dumbbell conformations. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories. 

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2. Nanoscale chromatin imaging and analysis platform bridges 4D chromatin organization with molecular function

   https://doi.org/10.1126/sciadv.abe4310  

   Li, Yue; Eshein, Adam; Virk, Ranya K.A.; Eid, Aya; Wu, Wenli; Frederick, Jane; VanDerway, David; Gladstein, Scott; Huang, Kai; Shim, Anne R.; et al (January 2021, Science Advances)

   null (Ed.)

   Extending across multiple length scales, dynamic chromatin structure is linked to transcription through the regulation of genome organization. However, no individual technique can fully elucidate this structure and its relation to molecular function at all length and time scales at both a single-cell level and a population level. Here, we present a multitechnique nanoscale chromatin imaging and analysis (nano-ChIA) platform that consolidates electron tomography of the primary chromatin fiber, optical super-resolution imaging of transcription processes, and label-free nano-sensing of chromatin packing and its dynamics in live cells. Using nano-ChIA, we observed that chromatin is localized into spatially separable packing domains, with an average diameter of around 200 nanometers, sub-megabase genomic size, and an internal fractal structure. The chromatin packing behavior of these domains exhibits a complex bidirectional relationship with active gene transcription. Furthermore, we found that properties of PDs are correlated among progenitor and progeny cells across cell division. 

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3. Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization

   https://doi.org/10.1038/s41467-024-48698-z  

   Kant, Aayush; Guo, Zixian; Vinayak, Vinayak; Neguembor, Maria Victoria; Li, Wing Shun; Agrawal, Vasundhara; Pujadas, Emily; Almassalha, Luay; Backman, Vadim; Lakadamyali, Melike; et al (December 2024, Nature Communications)

   Abstract In interphase nuclei, chromatin forms dense domains of characteristic sizes, but the influence of transcription and histone modifications on domain size is not understood. We present a theoretical model exploring this relationship, considering chromatin-chromatin interactions, histone modifications, and chromatin extrusion. We predict that the size of heterochromatic domains is governed by a balance among the diffusive flux of methylated histones sustaining them and the acetylation reactions in the domains and the process of loop extrusion via supercoiling by RNAPII at their periphery, which contributes to size reduction. Super-resolution and nano-imaging of five distinct cell lines confirm the predictions indicating that the absence of transcription leads to larger heterochromatin domains. Furthermore, the model accurately reproduces the findings regarding how transcription-mediated supercoiling loss can mitigate the impacts of excessive cohesin loading. Our findings shed light on the role of transcription in genome organization, offering insights into chromatin dynamics and potential therapeutic targets. 

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4. Interplay of condensate material properties and chromatin heterogeneity governs nuclear condensate ripening

   https://doi.org/10.1101/2024.05.07.593010  

   Banerjee, Deb Sankar; Chigumira, Tafadzwa; Lackner, Rachel M; Kratz, Josiah C; Chenoweth, David M; Banerjee, Shiladitya; Zhang, Huaiying (May 2024, bioRxiv)

   Nuclear condensates play many important roles in chromatin functions, but how cells regulate their nucleation and growth within the complex nuclear environment is not well understood. Here, we report how condensate properties and chromatin mechanics dictate condensate growth dynamics in the nucleus. We induced condensates with distinct properties using different proteins in human cell nuclei and monitored their growth. We revealed two key physical mechanisms that underlie droplet growth: diffusion-driven or ripening-dominated growth. To explain the experimental observations, we developed a quantitative theory that uncovers the mechanical role of chromatin and condensate material properties in regulating condensate growth in a heterogeneous environment. By fitting our theory to experimental data, we find that condensate surface tension is critical in determining whether condensates undergo elastic or Ostwald ripening. Our model also predicts that chromatin heterogeneity can influence condensate nucleation and growth, which we validated by experimentally perturbing the chromatin organization and controlling condensate nucleation. By combining quantitative experimentation with theoretical modeling, our work elucidates how condensate surface tension and chromatin heterogeneity govern nuclear condensate ripening, implying that cells can control both condensate properties and the chromatin organization to regulate condensate growth in the nucleus. 

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5. Interplay of condensate material properties and chromatin heterogeneity governs nuclear condensate ripening

   https://doi.org/10.7554/eLife.101777.1  

   Banerjee, Deb Sankar; Chigumira, Tafadzwa; Lackner, Rachel M; Kratz, Josiah C; Chenoweth, David M; Banerjee, Shiladitya; Zhang, Huaiying (November 2024, eLife)

   Nuclear condensates play many important roles in chromatin functions, but how cells regulate their nucleation and growth within the complex nuclear environment is not well understood. Here, we report how condensate properties and chromatin mechanics dictate condensate growth dynamics in the nucleus. We induced condensates with distinct properties using different proteins in human cell nuclei and monitored their growth. We revealed two key physical mechanisms that underlie droplet growth: diffusion-driven or ripening-dominated growth. To explain the experimental observations, we developed a quantitative theory that uncovers the mechanical role of chromatin and condensate material properties in regulating condensate growth in a heterogeneous environment. By fitting our theory to experimental data, we find that condensate surface tension is critical in determining whether condensates undergo elastic or Ostwald ripening. Our model also predicts that chromatin heterogeneity can influence condensate nucleation and growth, which we validated by experimentally perturbing the chromatin organization and controlling condensate nucleation. By combining quantitative experimentation with theoretical modeling, our work elucidates how condensate surface tension and chromatin heterogeneity govern nuclear condensate ripening, implying that cells can control both condensate properties and the chromatin organization to regulate condensate growth in the nucleus. 

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