A recent study conducted at the University of Texas Science Center, Houston, in the USA, has revealed that upon infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alters the host chromatin architecture to suppress antiviral interferon-responsive genes and augment inflammatory genes. The study is currently available on the bioRxiv* preprint server.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Background
SARS-CoV-2, the causative pathogen of coronavirus disease 2019 (COVID-19), is an enveloped, positive-sense, single-stranded RNA virus that primarily attacks epithelial cells in the human respiratory tract. From the perspective of viral evolution, it is well known that mutations appearing in SARS-CoV-2 spike protein under positive selection pressure are primarily responsible for increasing viral fitness into host cells. However, it is equally important to understand how SARS-CoV-2 modulates the host chromatin network to facilitate immune evasion and induce persistent clinical consequences.
The entire mammalian chromatin network contains several layers of architectures, including A/B compartments, Topological Associating Domains (TADs), and chromatin loops, which collectively regulate vital nuclear functions, including gene transcription, replication, recombination, and DNA damage repair.
In the current study, the scientists have investigated how SARS-CoV-2 affects the three-dimensional chromatin architecture of the host to improve immune fitness. They have assessed the host chromatin modification in angiotensin-converting enzyme 2 (ACE2)-expressing human alveolar epithelial cells that were infected with SARS-CoV-2.
Important observations
By conducting in situ Hi-C, the scientists detected and quantified the pairwise interactions between chromosome regions across the entire genome in virus-infected and mock-infected (control) cells. The findings revealed a significantly widespread alteration of the chromatic architecture in SARS-CoV-2-infected cells, with the highest deregulation in long-distance chromatic interactions. With further analysis, the scientists observed that chromatin domains are frequently weakened, and chromatin loops are frequently deregulated. Moreover, at the intra-chromosomal level, they observed a global reduction in short-distance chromatin interactions and an increase in mid-to-long distance and extremely long-distance interactions. Similarly, at the inter-chromosomal level, they observed an increased trans-chromosomal interaction. Collectively, these observations indicate SARS-CoV-2-induced alteration of chromatic compartmentalization.
Regarding chromatin compartmentalization defects, they noted a global reduction of A compartment and A-to-B switching, with 30% of genomic regions showing compartmental reduction or switching. By evaluating epigenomic characteristics of the regions susceptible to compartmental alterations, they observed that both A and B compartments are losing identity and switching to each other.
Epigenomic reprogramming
To understand the mechanism of compartmental alterations, the scientists conducted ChIP-Seq of active and repressive histone modifications as these modifications are enriched in A and B compartments, respectively. Interestingly, they observed that although overall modifications remained unchanged after infection, there was a significant reduction of H3K27ac, which is an active histone mark associated with higher transcriptional activation.
Simultaneously, they observed a moderate increase of recessive histone marks, including H3K9me3, following infection. Importantly, they observed a significant correlation between the weakening of the A compartment and the reduction of the active histone mark. Collectively, the findings indicate that SARS-CoV-2 induces compartmentalization defects by reprogramming chromatin modification.
Intra-TAD interactions
Regarding other chromatic structures, the scientists observed a global reduction in cis-interactions within TADs (intra-TAD interactions) after infection, which was accompanied by unchanged or increased cis-interactions outside of TADs. However, these changes were not associated with a loss of TAD identity. To understand the basis of reduced intra-TAD interactions, they assessed chromatin binding of two main TAD organizers, namely CTCF and cohesion. The findings revealed that a drastic depletion of cohesion from intra-TAD regions is primarily responsible for the weakening of interactions. Regarding epigenetic changes in virus-sensitive TADs, they identified that following infection, an induction of H3K9me3 is associated with cohesion depletion and subsequent reduction of intra-TAD interactions.
Immuno-pathological impacts of chromatin reprogramming
Two major immuno-pathological changes observed in severe COVID-19 patients include delayed or suppressed type 1 interferon response and excessive inflammation. In this study, the scientists developed three-dimensional genome and epigenome maps. They observed that SARS-CoV-2 infection caused transcriptional suppression of type 1 interferon-responsive antiviral genes and virus sensors by remarkably changing enhancer activity and enhancer–promotor interactions. Moreover, they noticed that SARS-CoV-2 caused transcriptional induction of inflammatory genes by uniquely and significantly increasing the H3K9me3 mark at their promoters.
Study significance
The study highlights a potential mechanism of SARS-CoV-2-mediated reprogramming of host chromatin network and its impact on immuno-pathological features of COVID-19. The study findings provide a novel path to further characterize persistent epigenomic impacts of SARS-CoV-2 infection.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- Apr 11 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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