Pilot study of DNA methylation in the pathogenesis of chronic rhinosinusitis with nasal polyps

Abstract

Background: DNA methylation has been implicated in the pathogenesis of allergy and atopy. This study aimed to identify whether DNA methylation also plays an important role in the pathogenesis of nasal polyps (NP). Methodology: NP tissues were obtained from 32 patients with chronic rhinosinusitis with bilateral NP. Biopsies of inferior turbinate mucosa (ITM) were taken from 18 patients who underwent rhinoseptoplasty (control group). The methylated genes, which were detected by DNA methylation microarray, were validated by methylation-specific polymerase chain reaction, bisulphite sequencing, real-time polymerase chain reaction and immunohistochemistry. Results: DNA methylation microarray identified 8,008 CpG islands in 2,848 genes. One hundred and ninety-eight genes were found to have a methylated signal in the promoter region in NP samples compared with ITM samples. The four top genes that changed, COL18A1, EP300, GNAS and SMURF1, were selected for further study. The methylation frequency of COL18A1 was significantly higher in NP samples than in ITM samples. Conclusions: DNA methylation might play an important role in the pathogenesis of NP. Promoter methylation of COL18A1 was found to be significantly increased in NP tissues, further studies are necessary to confirm the significance of these epigenetic factors in the mechanisms underlying the development or persistence of NP.

Genome-wide Epigenetic Study of Chronic Rhinosinusitis Tissues Reveals Dysregulated Inflammatory, Immunologic and Remodeling Pathways

“…The identification of epigenetic changes and effects on gene silencing or expression opens up the potential of novel targeted drugs such as DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. 21,22,46 In accordance with prior CRS epigenetic studies, 18,19,21,[25][26][27][30][31][32]47 we compared ethmoidal tissue from CRS subjects with IT from controls. We noted both hypermethylation and hypomethylation differences in CRS tissue compared to controls.…”

“…A scant number of studies in asthma have investigated single-cell DNA methylation. However, all genome wide methylation studies in CRS have used bulk tissue 17,32,47 and other DNA methylation studies in CRS have also used it. 23 We did not replicate or validate our current findings.…”

“…2 While epigenetic studies in CRS offer a unique approach to understanding CRS etiopathogenesis, these investigations have been primarily conducted on small populations in Asia. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Only one epigenetic study comprising of samples from 14 CRSwNP patients and 3 controls has been previously reported from the United States in 2012. The investigators reported elevated 5-bromocytosine and 5-chlorocytosine in CRSwNP.…”

DNMTs Are Involved in TGF-β1-Induced Epithelial–Mesenchymal Transitions in Airway Epithelial Cells

“…It is known that changes in gene expression caused by methylation can lead to cellular overgrowth and widespread inflammation in the respiratory tract [ 22 ]. In the nasal mucosal tissues of CRS patients, 2848 genes showed differential methylation, which was mainly functionally characterized as being associated with inflammation [ 23 ]. In a report related to DNA methylation associated with CRS, differences in DNA methylation were observed between the eosinophilic CRSwNP and non-eosinophilic CRSwNP, resulting in different pathological characteristics [ 24 ].…”

Epigenetic modifications in chronic rhinosinusitis with and without nasal polyps

“…One study has reported higher methylation levels of 198 genes in the promoter regions in NPs, compared to those in inferior turbinate mucosa samples, and the top four most hypermethylated genes are collagen type XVIII alpha 1 chain (COL18A1), E1A-binding protein p300 (EP300), alpha subunit of the GTP-binding stimulatory protein (GNAS) and Smad ubiquitination regulatory factor 1 (SMURF1). COL18A1, with a higher methylation frequency than the others, has inspired the exploration into the mechanisms of CRSwNP ( Zheng et al, 2015 ). Another report has also shown the DNA methylation levels at all CpG sites are higher in NPs compared with those in inferior turbinate mucosa, with tissue-type plasminogen activator (t-PA, gene name PLAT) as the most obvious ( Kidoguchi et al, 2018 ).…”