The conformation of the mammalian 3D genome is highly regulated and has a key role in various biological processes, such as transcription, DNA replication or repair, cell division or cell differentiation. By high-throughput chromosome conformation capture (Hi-C) and analysis, chromatin architecture is structured into A compartments (transcriptionally active euchromatin) and B compartments (transcriptionally inactive heterochromatin), as well as topological-associating domains (TADs) and chromatin loops. It has been shown that some viruses (such as influenza virus) may affect host chromatin; however, it remains elusive whether SARS-CoV-2 restructures the 3D architecture of host chromatin, and if so, how the virus achieves this or what this means to the host cells. In this new study, Wang, Lee et al. characterized the 3D chromatin organization of human cells after acute infection with SARS-CoV-2 using Hi-C and chromatin immunoprecipitation and sequencing (ChIP-seq) methods, and they found that SARS-CoV-2 restructures host chromatin.

The authors first showed that following SARS-CoV-2 infection chromatin compartmentalization was altered. Specifically, they found that interactions within A compartments were reduced or compartments A and B were mixed, whereas the B–B interactions remained unchanged. This suggests that SARS-CoV-2 infection weakens the (transcriptionally active) euchromatin of the host cells. In contrast to SARS-CoV-2, infection with the common-cold virus HCoV-OC43 did not elicit such changes, which suggests that this effect is quite specific to SARS-CoV-2.

Credit: Philip Patenall/Springer Nature Limited

To further understand the epigenetic mechanisms underlying the observed changes, the authors next investigated active histone modifications (H3K4me3 and H3K27ac) and repressive histone modifications (H3K9me3 and H3K27me3) before and after SARS-CoV-2 infection. Their analysis revealed that while most histone marks remained unchanged, the active histone mark H3K27ac was reduced in infected cells. This finding is in agreement with the observation that the transcriptionally active A compartment was weakened and the decrease in A–A compartmental interactions. Together, the findings suggest that SARS-CoV-2 disrupts the compartmentalization of host chromatin, likely by reprogramming chromatin modifications.

Moreover, the authors reported that intra-TAD chromatin interactions were reduced following infection. One of the main regulators of TADs is the ring-shaped ATPase cohesin, which has been shown to form DNA loops by extrusion. Interestingly, the cohesin complex was depleted from intra-TAD regions in infected cells, which might explain the observed reduction in intra-TAD interactions. In addition, the authors also hypothesize that the observation that chromatin in infected cells displayed a higher frequency of long-distance intra-chromosomal and inter-chromosomal interactions is possibly due to the decreased cohesin levels and consequently defective loop extrusion inside TADs.

Finally, the authors reported that the chromatin architecture changes following SARS-CoV-2 infection may provide a new perspective to understand the decreased activation of interferon response genes and the increased expression of pro-inflammatory genes. These two gene groups have crucial roles in the immunopathology of patients with COVID-19. Indeed, for interferon gene loci, often cohesin occupancy within the TADs in those regions was decreased and H3K27ac was reduced at nearby putative enhancers, which possibly results in their transcriptional inhibition. The authors also reported increased levels of H3K4me3 at the promoters of pro-inflammatory genes in infected cells, which suggests that SARS-CoV-2 enhances the promoter activity of those genes to increase their transcription.

In sum, the study reported the impact of SARS-CoV-2 infection on the host chromatin and epigenome, and future studies are now needed to fully uncover the mechanisms of viral-induced rewiring of host chromatin structures and their consequences.