Browsing by Author "Pierro, Michele Di"

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    An associative memory Hamiltonian model for DNA and nucleosomes
    (PLOS, 2023) Lu, Weiqi; Onuchic, José N.; Pierro, Michele Di; Center for Theoretical Biological Physics
    A model for DNA and nucleosomes is introduced with the goal of studying chromosomes from a single base level all the way to higher-order chromatin structures. This model, dubbed the Widely Editable Chromatin Model (WEChroM), reproduces the complex mechanics of the double helix including its bending persistence length and twisting persistence length, and the temperature dependence of the former. The WEChroM Hamiltonian is composed of chain connectivity, steric interactions, and associative memory terms representing all remaining interactions leading to the structure, dynamics, and mechanical characteristics of the B-DNA. Several applications of this model are discussed to demonstrate its applicability. WEChroM is used to investigate the behavior of circular DNA in the presence of positive and negative supercoiling. We show that it recapitulates the formation of plectonemes and of structural defects that relax mechanical stress. The model spontaneously manifests an asymmetric behavior with respect to positive or negative supercoiling, similar to what was previously observed in experiments. Additionally, we show that the associative memory Hamiltonian is also capable of reproducing the free energy of partial DNA unwrapping from nucleosomes. WEChroM is designed to emulate the continuously variable mechanical properties of the 10nm fiber and, by virtue of its simplicity, is ready to be scaled up to molecular systems large enough to investigate the structural ensembles of genes. WEChroM is implemented in the OpenMM simulation toolkits and is freely available for public use.
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    Walking along chromosomes with super-resolution imaging, contact maps, and integrative modeling
    (Public Library of Science, 2018) Nir, Guy; Farabella, Irene; Estrada, Cynthia Pérez; Ebeling, Carl G.; Beliveau, Brian J.; Sasaki, Hiroshi M.; Lee, S. Dean; Nguyen, Son C.; McCole, Ruth B.; Chattoraj, Shyamtanu; Erceg, Jelena; Abed, Jumana AlHaj; Martins, Nuno M.C.; Nguyen, Huy Q.; Hannan, Mohammed A.; Russell, Sheikh; Durand, Neva C.; Rao, Suhas S.P.; Kishi, Jocelyn Y.; Soler-Vila, Paula; Pierro, Michele Di; Onuchic, José N.; Callahan, Steven P.; Schreiner, John M.; Stuckey, Jeff A.; Yin, Peng; Aiden, Erez Lieberman; Marti-Renom, Marc A.; Wu, C.-ting
    Chromosome organization is crucial for genome function. Here, we present a method for visualizing chromosomal DNA at super-resolution and then integrating Hi-C data to produce three-dimensional models of chromosome organization. Using the super-resolution microscopy methods of OligoSTORM and OligoDNA-PAINT, we trace 8 megabases of human chromosome 19, visualizing structures ranging in size from a few kilobases to over a megabase. Focusing on chromosomal regions that contribute to compartments, we discover distinct structures that, in spite of considerable variability, can predict whether such regions correspond to active (A-type) or inactive (B-type) compartments. Imaging through the depths of entire nuclei, we capture pairs of homologous regions in diploid cells, obtaining evidence that maternal and paternal homologous regions can be differentially organized. Finally, using restraint-based modeling to integrate imaging and Hi-C data, we implement a method-integrative modeling of genomic regions (IMGR)-to increase the genomic resolution of our traces to 10 kb.