Exploring chromosomal structural heterogeneity across multiple cell lines
Year: 2020
Type: article
Abstract: We study the structural ensembles of human chromosomes across different cell types. Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using a combination of machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. The chromosomal structures obtained in silico are quantitatively consistent with those obtained through microscopy as well as DNA-DNA proximity ligation assays. 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 transitions between a closed conformation and an open dumbbell conformation. This conformational transition appears to be consistent with a two-state process with an effective free energy cost of about four times the effective information theoretic temperature. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. Genetically identical but epigenetically distinct cell types appear to rearrange their respective structural ensembles to expose segments of transcriptionally active chromatin, belonging to the A genomic compartment, towards the surface of the chromosome, while inactive segments, belonging to the B compartment, move to the interior. 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.
Source: eLife
DOI: 10.7554/elife.60312
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: National Science Foundation, U.S. Department of Agriculture, Welch Foundation, Cancer Prevention and Research Institute of Texas, United States-Israel Binational Science Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health, Center for Theoretical Biological Physics, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, NIH Office of the Director, Division of Chemistry
Awards: G1152932680, G1251237492, G152678301, Beyond pairwise DNA contacts: exploring higher-order genome structure using proximity ligation, G2837517328, G294349639, G3120809956, G3365519157, The energy landscape for folding and function of biomolecules: integrating physical models, genetic information and experiments, G4152014458, G4282993402, GENOME WIDE MAPPING OF LOOPS USING IN SITU HI-C, G500433559, G508817667, G5275090706, Center for Theoretical Biological Physics, Exploring how the genome folds through proximity ligation and sequencing, G6747575208, G7552767333, G8268201320, Recruitment of First-Time, Tenure-Track Faculty Members, G930930142
OpenAlex ID: W3092433196