SARS-CoV-2 has made >190-million infections worldwide, thus it is pivotal to understand the viral impacts on host cells.

Many viruses can significantly alter host chromatin, but such roles of SARS-CoV-2 are largely unknown.

Here, we characterized the three-dimensional (3D) genome architecture and epigenome landscapes in human cells after SARS-CoV-2 infection, revealing remarkable restructuring of host chromatin architecture.

High-resolution Hi-C 3.0 uncovered widespread A compartmental weakening and A-B mixing, together with a global reduction of intra-TAD chromatin contacts.

The cohesin complex, a central organizer of the 3D genome, was significantly depleted from intra-TAD regions, supporting that SARS-CoV-2 disrupts cohesin loop extrusion.

Calibrated ChIP-Seq verified chromatin restructuring by SARS-CoV-2 that is particularly manifested by a pervasive reduction of euchromatin modifications.

Built on the rewired 3D genome/epigenome maps, a modified activity-by-contact model highlights the transcriptional weakening of antiviral interferon response genes or virus sensors (e.g., DDX58) incurred by SARS-CoV-2. In contrast, pro-inflammatory genes (e.g. IL-6) high in severe infections were uniquely regulated by augmented H3K4me3 at their promoters.

These findings illustrate how SARS-CoV-2 rewires host chromatin architecture to confer immunological gene deregulation, laying a foundation to characterize the long-term epigenomic impacts of this virus.

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