Yale Researchers Warn Of DNA Methylation Dysregulation In Long COVID

COVID-19 News: Long COVID, also known as Post-Acute Sequelae of COVID-19 (PASC), has emerged as a global health challenge, affecting millions of survivors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The syndrome presents with a myriad of clinical signs and symptoms, making its pathology and prognosis difficult to decipher. In this COVID-19 News report, we delve into the intricate world of epigenetics, specifically focusing on DNA methylation (DNAm) dysregulation, as researchers from the Yale School of Public Health caution about its potential role in the persistence and manifestation of long COVID.


Lower methylation level of the CpG islands in the DNA promoter sequence increases the expression level of ACE2 and interferon genes, which may lead to higher susceptivity to SARS-CoV-2 infection, and may influence risk of long COVID.

Understanding Long COVID
Long COVID is characterized by persistent symptoms that endure beyond the acute phase of COVID-19 recovery. With limited reliable biomarkers for identifying long COVID, its full pathogenicity remains unclear. Approximately 10%-20% of symptomatic SARS-CoV-2 infections result in long COVID, with a higher risk observed among hospitalized and unvaccinated individuals.
 
The Impact on Daily Life
Long COVID can qualify as a disability under the Americans with Disabilities Act (ADA), significantly impacting major life activities. Studies show associations between long COVID and reduced employment, emphasizing the need for a deeper understanding of the syndrome's mechanisms.
 
Clinical Complexity
The vast variability in symptoms and duration, coupled with the absence of biomarkers and diagnostic tests, complicates clinical and public health perspectives on long COVID. Fatigue, cognitive impairment, joint pain, and anxiety are prevalent symptoms, persisting for years in some cases. The underlying pathophysiology involves neuronal damage, immune dysregulation, disruption in the human microbiota, microvascular blood clotting, and persistent viral replication or immune stimulation.
 
Prevention and Biomarkers
Preventing SARS-CoV-2 infection remains the most effective strategy against long COVID, with immunization reducing symptom severity and the likelihood of long-term complications. However, identifying reliable biomarkers for long COVID has been challenging. A systematic review in 2023 identified 113 biomarkers associated with long COVID, with cytokines/chemokines showing potential as diagnostic markers.
 
Epigenetics and the DNAm Landscape
Epigenetics explores the regulation of gene expression and its impact on diseases, including COVID-19. DNA methylation, a key epigenetic characteristic, involves adding a methyl group to cytosine bases in DNA, influencing gene regulation. In this review, we examine the role of DNAm in the context of long COVID and its potential contributions to understanding the syndrome&# 39;s pathology and prognosis.
 
DNAm Dysregulation in Acute SARS-CoV-2 Infection
The interaction between SARS-CoV-2 and host cells involves intricate epigenetic phenomena, including DNA methylation. Studies have identified DNAm patterns associated with COVID-19, revealing changes in interferon-related genes, ACE2, and inflammatory cytokine genes. CpG sites, crucial in genetic phenomena, have been implicated in diverse processes, with genome-wide profiling distinguishing COVID-19 cases from uninfected controls.
 
Insights from DNAm Studies in Long COVID Patients
Research focusing on DNA methylation (DNAm) in long COVID patients is still in its infancy, with limited studies shedding light on the potential epigenetic alterations induced by COVID-19. However, preliminary findings suggest that the virus may leave a lasting imprint on the epigenome, contributing to the persistence of long-term symptoms observed in some individuals.
 
A notable study conducted in Norway compared DNAm profiles between individuals experiencing persistent long COVID symptoms and those who had experienced remission. This study identified differentially methylated regions (DMRs), regions of the genome where methylation patterns differ between groups, suggesting distinct epigenetic signatures associated with long COVID. These findings provide valuable insights into the molecular mechanisms underlying the syndrome's pathogenesis and may pave the way for the development of targeted interventions.
 
Furthermore, another study explored the DNAm profiles of individuals with persistent long COVID symptoms compared to convalescent individuals who had recovered from acute COVID-19. This investigation revealed unique DNAm patterns between the two groups, further emphasizing the role of epigenetic modifications in shaping the clinical trajectory of COVID-19 survivors. These distinct DNAm profiles may serve as potential biomarkers for identifying individuals at risk of developing long COVID or predicting the severity and duration of symptoms.
 
Moreover, researchers have observed epigenetic aging acceleration and telomere attrition in long COVID patients, indicating potential long-lasting molecular imprints left by the virus. Epigenetic aging refers to changes in DNAm patterns associated with aging, which can be accelerated or decelerated by various environmental factors, including viral infections. Telomeres, the protective caps at the end of chromosomes, are known to shorten with age and cellular stress, and telomere attrition has been linked to various age-related diseases and conditions. The observation of accelerated epigenetic aging and telomere attrition in long COVID patients underscores the systemic impact of SARS-CoV-2 infection on the body's biological aging processes.
 
Collectively, these preliminary findings highlight the importance of investigating DNAm alterations in long COVID patients to unravel the underlying molecular mechanisms driving the persistence of symptoms.
https://pubmed.ncbi.nlm.nih.gov/35871090/
 
https://pubmed.ncbi.nlm.nih.gov/36517875/
 
https://pubmed.ncbi.nlm.nih.gov/35440567/
 
https://pubmed.ncbi.nlm.nih.gov/33464637/
 
https://pubmed.ncbi.nlm.nih.gov/36263014/
 
Long-Term DNAm Changes in Other Coronavirus Infections
Exploring the epigenetic landscape of other coronavirus infections, such as SARS and MERS, provides valuable insights. While limited observational studies focus on epigenetic markers in survivors of SARS and MERS, the knowledge gained can contribute to understanding long-term symptomatic survivors of COVID-19.
 
Conclusion and Future Directions
In conclusion, unraveling the epigenetic enigma of long COVID through the lens of DNA methylation offers promising avenues for understanding its complex manifestations. Large-scale epigenome-wide association studies (EWAS) focusing on diverse long COVID samples, investigations into the interaction between vaccination and prior infection history, and meta-analyses pooling long COVID EWAS are recommended for a deeper understanding of DNAm and key epigenetic insights. As we navigate the complexities of long COVID, the exploration of epigenetic mechanisms may pave the way for targeted interventions and improved outcomes for those grappling with the aftermath of SARS-CoV-2 infection.
 
The study review was published in the peer reviewed journal: Frontiers in Virology.
https://www.frontiersin.org/articles/10.3389/fviro.2024.1371683/full
 
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