DNA Methylation of ProximalPLATPromoter in Chronic Rhinosinusitis With Nasal Polyps

Abstract

Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in other tissues. Objective We aimed to investigate the methylation levels in the proximal PLAT promoter and their effects on gene expression in NP tissue. Methods We investigated the methylation levels at 3 CpG sites in the proximal PLAT promoter regions (-618, -121, and -105 with respect to the transcription initiation site) by bisulfite pyrosequencing and their effects on the gene expression by quantitative real-time polymerase chain reaction (qPCR) in 20 paired samples of NP and inferior turbinate tissue (IT) from patients with CRS. Results The DNA methylation levels at all CpG sites were higher ( P < .01), and the PLAT expression was lower ( P < .001) in NP compared with IT. The methylation changes at the -618 site showed a negative correlation with the gene expression changes between NP and IT ( r = -.65, P < .01). Conclusions Hypermethylation of PLAT promoter may downregulate the gene expression in NP, leading to excessive fibrin deposition by aberrant coagulation cascade. DNA methylation of proximal PLAT promoter may contribute to NP growth and have a potential as a new therapeutic target.

International consensus statement on allergy and rhinology: rhinosinusitis 2021

“…It is of significant interest that cigarette smoking and S. aureus , factors associated with increased severity of CRS, are both implicated in epigenetic modification. Evidence of epigenetics in‐vivo is still limited, but nevertheless, the concepts suggested by these studies are intriguing and hold promise for the future 853,966–969 . Most studies assessing blood and/or nasal epithelia have identified that epigenetic changes are more pronounced in epithelium than in circulating blood, supporting the importance of contact with the external environment for their development.…”

Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin

“…88 It has been reported that DNA methylation changes were induced by type 2 cytokines in asthmatic airway tissues and might contribute to asthma phenotype. 89 Kidoguchi et al 90 have reported that the proximal promoter, especially at the -618 CpG site of PLAT (tPA; gene name PLAT), was hypermethylated in NPs, and the degree of methylation was negatively correlated with expression levels of PLAT. 90 They concluded that hypermethylation of the proximal PLAT promoter may lead to decreased gene expression in NPs, leading to abnormal fibrin deposition by impairment of fibrinolysis.…”

Adult‐onset eosinophilic airway diseases

“…124,125 Tissue plasminogen activator (tPA) is downregulated in NPs 121 by the hypermethylation of the proximal tPA gene promoter in NPs. 126 Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits the fibrinolysis cascade. The levels of TAFI are elevated in CRSwNP, especially CRSwNP with asthma.…”

“…The levels of thrombin and factor XIIIA are elevated in NPs and act in the final step of the formation of fibrin mesh 124,125 . Tissue plasminogen activator (tPA) is downregulated in NPs 121 by the hypermethylation of the proximal tPA gene promoter in NPs 126 . Thrombin‐activatable fibrinolysis inhibitor (TAFI) inhibits the fibrinolysis cascade.…”