Over the past few decades, we have learned that both structure and organization of DNA is critically important to cellular function. Not only does over six feet of DNA have to fit into the microscopic nucleus of a human cell, but this genetic material must be organized so certain pieces of it can be accessed when needed. This is the first step in “gene expression,” the process where information stored in DNA is translated into cellular function. Gene expression is tightly regulated, and genomic organization is just one critical aspect. The organization of DNA inside the nucleus, though dynamic, is highly ordered to set up interactions between proteins and the DNA sequences that they act on. The organization of DNA across space and time affects how proteins read, interact with, and use the genetic material.
What happens if genomic organization is altered in unintended ways? Disorganization of the genome could have a big impact on gene expression. In fact, this is a common weapon several types of viruses use in the arms race against hosts, including SARS-CoV-2. Work from a research team led by 4D Nucleome program (4DN) researcher Wenbo Li, Ph.D. showed that SARS-CoV-2 can restructure the genome of infected cells potentially to the benefit of the virus.[1] At the time, it was unclear how this advantage could be achieved. New computer modeling work by a team led by 4DN researcher Mario Nicodemi, Ph.D. now shows that SARS-CoV-2 infection restructures the genome in a way that increases its disorganization compared to the genomes of non-infected cells.[2] Host cells infected with SARS-CoV-2 have weakened interactions among a network of DNA contacts that normally maintain genome structure and control gene expression. In essence, SARS-CoV-2 can be thought of as scrambling parts of the regulated structure of the host’s genome.
This disorganization could mean that genetic messages are not correctly processed, and messages coming from genes responsible for the antiviral immune response may not be properly relayed. As a result, the host’s defenses against the virus could suffer, giving the virus an upper hand. Indeed, Dr. Nicodemi’s group found that the genomic structure of two critical immune response genes was highly variable compared to the structure of those two genes in uninfected cells.[2] According to the researchers, this variability likely impairs the programs that regulate these genes, resulting in inefficient messaging. The results of the group’s modeling studies may help explain some of the previously observed but unexplained dysfunction of antiviral immune responses to SARS-CoV-2 at a gene regulation level, though there are likely several additional explanations that could also be at play. Although these observations have not yet affected COVID-19 outcomes or treatments, this important work links genomic architecture across both space and time to human health, a primary goal of the NIH Common Fund’s 4DN program.
References
- SARS-CoV-2 restructures host chromatin architecture. Wang R, Lee JH, Kim J, Xiong F, Hasani LA, Shi Y, Simpson EN, Zhu X, Chen YT, Shivshankar P, Krakowiak J, Wang Y, Gilbert DM, Yuan X, Eltzschig HK, Li W. Nat Microbiol, 2023 Apr;8(4):679-694. doi: 10.1038/s41564-023-01344-8.
- Multiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells. Chiariello AM, Abraham A, Bianco S, Esposito A, Fontana A, Vercellone F, Conte M, Nicodemi M. Nat Commun, 2024 May;15(1):4014. doi: 10.1038/s41467-024-48370-6.
