Differential methylation as a mediator of COVID-19 susceptibility

Steyaert, Sandra; Trooskens, Geert; Delanghe, Joris; Criekinge, Wim Van

doi:10.1101/2020.08.14.251538

Cited by 5 publications

(5 citation statements)

References 23 publications

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“…ACE2 expression in the lung could be regulated by enzymes that modify histones, including HAT1, HDAC2, and KDM5B (40). In both freshly isolated airway epithelial cells and human lung tissues, different patterns of ACE2 gene methylation near the transcription start site of the ACE2 gene were identified in populations with different age and gender (41). MicroRNAs (miRNAs) could be involved in decreasing ACE2 expression at mRNA levels as well.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

Sui

Venzon

et al. 2021

Front. Immunol.

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SARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques. The expression levels of ACE2 and type I interferons were also found to be correlated with each other, consistent with the recent finding that ACE2 is an interferon-inducible gene. Furthermore, induction of ACE2 and type I interferons by poly I:C, an interferon inducer, was suppressed by S1 protein in primary cells of BAL. These observations suggest that the downregulation of ACE2 and type I interferons induced by S1 protein may directly contribute to SARS-CoV-2-associated lung diseases.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

Sui

Venzon

et al. 2021

Front. Immunol.

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“…These genes are also shown to be regulated by epigenetics [Zill et al, 2012; Chu et al, 2014]. It was predicted that there is differential methylation in ACE2 gene and that may be the cause of variability of its expression and it could be used to check the susceptibility of an individual to SARS-CoV-2 infection [Steyaert et al, 2020]. However, promoter DNA methylation of both ACE2 and TMPRSS2 was not quantified in subjects infected with SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation and gene expression pattern of ACE2 and TMPRSS2 genes in saliva samples of patients with SARS-CoV-2 infection

Misra

Mukherjee

Negi

et al. 2020

Preprint

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COVID-19 caused by SARS-CoV-2 became a pandemic affecting the health and economy of the world. Although it was known that this virus uses ACE2 protein along with TMPRSS2 to enter the host cell, the methylation pattern and gene expression of ACE2 and TMPRSS2 genes are not explored in saliva samples of patients infected with COVID-19. The study aimed to quantify promoter methylation of ACE2 and TMPRSS2 along with its mRNA expression in saliva samples of COVID-19 patients in order to understand the regulatory mechanism of these genes in SARS-CoV-2 infection. Saliva samples were collected from thirty male patients with SARS-CoV-2 infection and thirty age-matched healthy control male subjects. Q MS PCR and qRT PCR was performed to quantify the promoter DNA methylation and mRNA expression of ACE2 and TMPRSS2 respectively. Our study didnot find any significant difference between methylation and expression of these two genes in cases compared to control subjects. However there was significant positive correlation between DNA methylation of ACE2 and its gene expression. Among cases, the sample collected more than or equal to 7 days after appearance of symptoms showed higher amount of methylation in both ACE2 and TMPRSS2 genes when compared to sample collected before 7 days. In conclusion, we found that ACE2 and TMPRSS2 methylation plays a role in COVID-19.

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“…Along these findings, ACE2 profiles were also shown to display a significant correlation with histone modification-related genes in the human lungs [90]. Additionally, the results of another study have previously demonstrated that ACE2 promoter was hypermethylated in hypertensive patients with a significant difference between males and females [91], where COVID-19 patients as well have displayed differential methylation pattern in ACE2 of blood samples [92] which further requires testing in the respiratory samples.…”

Section: Epigenetic Variation Of Ace2mentioning

confidence: 70%

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Badawi

Ali

2021

Hum Genomics

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With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

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Differential methylation as a mediator of COVID-19 susceptibility

Cited by 5 publications

References 23 publications

SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

DNA methylation and gene expression pattern of ACE2 and TMPRSS2 genes in saliva samples of patients with SARS-CoV-2 infection

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

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