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Currently, the COVID-19 pandemic is the most discussed subject in medical researches worldwide. As the knowledge is expanded about the disease, more hypotheses become created. A recent study on the viral protein interaction map revealed that SARS-CoV-2 open reading frame 8 (ORF8) interacts with human DNA methyl transferase1 (DNMT1), an active epigenetic agent in DNA methylation. Moreover, DNMT1 is a contributor to a variety of chronic diseases which could cause some epigenetic dysregulation in infected cells, especially leukocytes, pancreatic beta, and endothelial cells. Regarding the fact that epigenetic alterations have a partial, but not completely reversible phenomena, it raises the question that if this interaction may cause long-term complications such as diabetes, atherosclerosis, cancer, and autoimmune diseases. Accordingly, long follow-up studies on the recovered patients from COVID-19 are recommended.