BREAKING! University Of Texas Study Discovers That SARS-CoV-2 Alters Human Host Chromatin Complex To Cause Immune Dysfunction!

An alarming study finding of a recent research conducted by scientist from the University of Texas Science Center, Houston-USA, has revealed that upon infection, the SARS-CoV-2 coronavirus alters the host chromatin architecture to suppress antiviral interferon-responsive genes and augment inflammatory genes. The process that SARS-CoV-2 deploys is similar to what can be termed as epigenomic reprogramming, says the study team.

 
Such altering of the human chromatin also has serious concerning implications about a variety of possible medical and health conditions rising in the long term of those who have been infected with the SARS-CoV-2 coronavirus.
 
There is however no data as yet available indicating if simply spike proteins from the SARS-CoV-2 alone can induce these epigenomic reprogramming  changes alone.(It should noted that the virus spike proteins are being used in a variety of vaccines at the moment.)
 
Numerous viruses can significantly alter host chromatin, but such roles of the SARS-CoV-2 are largely unknown until now.
 
The study team 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.

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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.
 
On the other hand, pro-inflammatory genes (e.g. IL-6) high in severe infections were uniquely regulated by augmented H3K4me3 at their promoters.
 
The study findings illustrate how the SARS-CoV-2 coronavirus  rewires host chromatin architecture to confer immunological gene deregulation, laying a foundation to characterize the long-term epigenomic impacts of this virus.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.07.20.453146v1
 
The SARS-CoV-2 coronavirus, the causative pathogen of COVID-19 disease, is an enveloped, positive-sense, single-stranded RNA virus that primarily attacks epithelial cells in the human resp iratory 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.
 
It is  however equally important to understand how SARS-CoV-2 modulates the host chromatin network to facilitate immune evasion and induce persistent clinical consequences.
 
It is already known that 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.
 
The study team investigated how SARS-CoV-2 affects the three-dimensional chromatin architecture of the host to improve immune fitness. They assessed the host chromatin modification in angiotensin-converting enzyme 2 (ACE2)-expressing human alveolar epithelial cells that were infected with SARS-CoV-2.
 
Utilizing in situ Hi-C, the study team detected and quantified the pairwise interactions between chromosome regions across the entire genome in virus-infected and mock-infected (control) cells.
 
The study 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.
 
Further detailed analysis, revealed that the chromatin domains are frequently weakened, and chromatin loops are frequently deregulated. Moreover, at the intra-chromosomal level, the study team observed a global reduction in short-distance chromatin interactions and an increase in mid-to-long distance and extremely long-distance interactions.
 
Also, at the inter-chromosomal level, the study team observed an increased trans-chromosomal interaction. Collectively, these observations indicate SARS-CoV-2-induced alteration of chromatic compartmentalization.
 
With regards to chromatin compartmentalization defects, the study team 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, the team observed that both A and B compartments are losing identity and switching to each other.
 
In order to understand the mechanism of compartmental alterations, the study team conducted ChIP-Seq of active and repressive histone modifications as these modifications are enriched in A and B compartments, respectively.

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Interestingly, the study team 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.
 
Importantly the team also observed a moderate increase of recessive histone marks, including H3K9me3, following infection.
 
The study team 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.
 
Pertaining to other chromatic structures, the study team 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.
 
In order to understand the basis of reduced intra-TAD interactions, the team assessed chromatin binding of two main TAD organizers, namely CTCF and cohesion.
 
The study findings revealed that a drastic depletion of cohesion from intra-TAD regions is primarily responsible for the weakening of interactions.
 
With regards to epigenetic changes in virus-sensitive TADs, the study team identified that following infection, an induction of H3K9me3 is associated with cohesion depletion and subsequent reduction of intra-TAD interactions.
           
Most significantly, two major immuno-pathological changes observed in severe COVID-19 patients include delayed or suppressed type 1 interferon response and excessive inflammation.
 
In the study, the study team developed three-dimensional genome and epigenome maps. The team 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.
 
Furthermore, the study team noticed that SARS-CoV-2 caused transcriptional induction of inflammatory genes by uniquely and significantly increasing the H3K9me3 mark at their promoters.
 
The findings highlight a potential mechanism of SARS-CoV-2-mediated reprogramming of host chromatin network and its impact on immuno-pathological features of COVID-19.
 
Most importantly, the study findings provide a novel path to further characterize persistent epigenomic impacts of SARS-CoV-2 infection.

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