While the cough was the cardinal consideration, COVID-19 has been causing chaos in every organ system, including lungs, heart, brain, blood, liver, and skin. In fact, the involvement of these non-lung systems predicts increased mortality and new research now shows that DNA methylation is a contributor to COVID-19.
Researchers from the laboratory of Arjun Deb at UCLA are now the first to model the widespread COVD-19 induced defects in organ systems beyond the lungs in mice. The SARS-CoV-2 virus that is responsible for COVID-19 relies on the ACE2 receptor protein to infect humans but doesn’t recognize the mouse version. To make use of established mouse models, the talented team incorporated the human ACE2 (hACE2) transgene into mice. The mice were injected with SARS-CoV-2, becoming hACE2/SARS-CoV-2 mice. After just seven days, these mice have many of the outcomes observed in human COVID-19 patients:
- Decreased food consumption, body weight, body fat, activity
- Blood – more granulocytes and fewer lymphocytes
- Suboptimal immune activation
- Cardiac problems, including myocyte cell death, myofibrillar disarray, heart swelling, thickened ventricular walls, depressed heart rate and low blood pressure
To understand these changes on a molecular level, these inspiring investigators first looked for gene expression changes using bulk RNA-sequencing. They found distinct patterns depending on time and tissue, specifically:
- Anti-viral immune response within 3 days of SARS-CoV-2 injection
- Decreased expression of citric acid cycle enzymes and reduced levels of their direct metabolites
- Decreased expression of mitochondrial genes in the heart
- No changes in mitochondria number or structure
Given the changes in gene expression, the authors turned to DNA methylation as a potential regulator. Using reduced representation bisulfite sequencing (RRBS), they looked for differentially methylated sites and found:
- 172 differentially methylated sites in the heart and 49 in the kidney
- 26 and 3, respectively, overlap with differentially expressed genes
- Peg10 and Ece1 each associate with multiple methylation sites
- Peg10 is a retrotransposon-derived paternally expressed imprinted gene that regulates cell proliferation
- Ece1 loss of function associates with cardiac defects
This exciting work on COVID-19 shows that not only can COVID-19 be modelled in mice, but that the outcomes may be the result of epigenetic changes that contribute to toxicity in specific organ systems and overall lethality.
Check out the epigenetics of COVID-19 in JCI Insight, December 2020.