SARS-CoV-2 Restructures the Host Chromatin Architecture

Abstract

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.

Integrated multi-omics analyses identify key anti-viral host factors and pathways controlling SARS-CoV-2 infection

“…By leveraging viral RNA and protein interactomes, we found that six anti-viral factors identi ed in this study belong to the cohesin complex, a central organizer of the three-dimensional (3D) genome structure 31 . Consistent with our nding, a recent study showed that SARS-CoV-2 was able to rewire host chromatin organization in human cells to confer immunological gene deregulation 32 . Our nding of the subunits of the cohesin complex as inhibitors of SARS-CoV-2 infection provides the rst functional evidence to directly support the role of 3D chromatin organization in mediating host-virus interactions.…”

SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

“…Fitting with previous work indicating that ORF8 affects endoplasmic reticulum (ER) stress pathways 32 , this suggests that ORF8 probably has an ARKSAP-independent function that may promote viral particle formation. Taken together, this work presents a link between a specific SARS-CoV-2 protein and the epigenetic disruptions that occur in response to infection and provides a mechanistic explanation for mounting evidence 12,13,45 that epigenetic disruptions contribute to the severity of COVID-19.…”

Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer

“…Viruses have been demonstrated to hijack and re-wire the 3D chromatin organization of the host cell for subverting its immune defense system and exerting long-term inflammatory and other gene regulatory effects ( Heinz et al, 2018 ; Liu et al, 2020 ). In light of the ongoing COVID-19 pandemic, Wang et al (2021) recently reported that SARS-CoV-2 infected cells showed a significant ablation of cohesin, another architectural protein complex that collaborates with CTCF to mediate DNA looping ( Dekker and Mirny, 2016 ), within TADs, causing a widespread weakening of intra-TAD chromatin interactions. Furthermore, A/B compartmentalization manifested a drastic perturbation in the form of A-to-B switching, resulting in erosion of the euchromatic A compartment that is coupled with a global decrease in the active histone H3K27ac mark.…”