DNA methylation changes during acute COVID-19 are associated with long-term transcriptional dysregulation in patients' airway epithelial cells.

Summary

Using enzymatic methylome profiling and single-cell RNA-seq of nasal epithelium, the study identified 3,112 differentially methylated regions in COVID-19, with hypermethylation of ciliary genes that remained transcriptionally repressed in ciliated cells up to 12 months post-infection. An independent cohort validated symptom-dependent repression, implicating acute epigenetic changes in long-term airway dysfunction.

Key Findings

• Identified 3,112 differentially methylated regions in nasal epithelial cells of COVID-19 patients versus controls.
• Ciliary function genes were hypermethylated and remained transcriptionally repressed in ciliated cells up to 12 months post-infection.
• An independent 6-month post-infection cohort validated symptom-dependent repression of ciliary genes.

Clinical Implications

Highlights mucociliary dysfunction as a target for monitoring and potential intervention in post-COVID care; motivates exploration of epigenetic-modifying or ciliary-supporting therapies.

Limitations

• Modest sample sizes limit generalizability and causal inference
• Nasal epithelium may not fully represent lower airway biology; functional rescue experiments were not reported

Future Directions

Test reversibility of ciliary gene repression with epigenetic modulators, extend to lower airway samples, and correlate with longitudinal clinical phenotypes of post-COVID respiratory symptoms.