Multiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells

Andrea M. Chiariello (), Alex Abraham, Simona Bianco, Andrea Esposito, Andrea Fontana, Francesca Vercellone, Mattia Conte and Mario Nicodemi ()
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Andrea M. Chiariello: Complesso Universitario di Monte Sant’Angelo
Alex Abraham: Complesso Universitario di Monte Sant’Angelo
Simona Bianco: Complesso Universitario di Monte Sant’Angelo
Andrea Esposito: Complesso Universitario di Monte Sant’Angelo
Andrea Fontana: Complesso Universitario di Monte Sant’Angelo
Francesca Vercellone: Università degli Studi di Napoli Federico II, and INFN Napoli
Mattia Conte: Complesso Universitario di Monte Sant’Angelo
Mario Nicodemi: Complesso Universitario di Monte Sant’Angelo

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract SARS-CoV-2 can re-structure chromatin organization and alter the epigenomic landscape of the host genome, but the mechanisms that produce such changes remain unclear. Here, we use polymer physics to investigate how the chromatin of the host genome is re-organized upon infection with SARS-CoV-2. We show that re-structuring of A/B compartments can be explained by a re-modulation of intra-compartment homo-typic affinities, which leads to the weakening of A-A interactions and the enhancement of A-B mixing. At the TAD level, re-arrangements are physically described by a reduction in the loop extrusion activity coupled with an alteration of chromatin phase-separation properties, resulting in more intermingling between different TADs and a spread in space of the TADs themselves. In addition, the architecture of loci relevant to the antiviral interferon response, such as DDX58 or IFIT, becomes more variable within the 3D single-molecule population of the infected model, suggesting that viral infection leads to a loss of chromatin structural specificity. Analysing the time trajectories of pairwise gene-enhancer and higher-order contacts reveals that this variability derives from increased fluctuations in the chromatin dynamics of infected cells. This suggests that SARS-CoV-2 alters gene regulation by impacting the stability of the contact network in time.

Date: 2024
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DOI: 10.1038/s41467-024-48370-6

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