Abstract

Chronic rhinosinusitis (CRS) pathogenesis is closely related to tissue remodeling, including epithelial–mesenchymal transition (EMT). Epigenetic mechanisms play key roles in EMT. DNA methylation, mediated by DNA methyltransferases (DNMTs), is an epigenetic marker that is critical to EMT. The goal of this study was to determine whether DNMTs were involved in TGF-β1-induced EMT and elucidate the underlying mechanisms in nasal epithelial cells and air–liquid interface cultures. Global DNA methylation and DNMT activity were quantified. DNMT expression was measured using real-time PCR (qRT–PCR) in human CRS tissues. mRNA and protein levels of DNMTs, E-cadherin, vimentin, α-SMA, and fibronectin were determined using RT–PCR and Western blotting, respectively. DNMT1, DNMT3A, and DNMT3B gene expression were knocked down using siRNA transfection. MAPK phosphorylation and EMT-related transcription factor levels were determined using Western blotting. Signaling pathways were analyzed using specific inhibitors of MAPK. We demonstrated these data in primary nasal epithelial cells and air–liquid interface cultures. Global DNA methylation, DNMT activity, and DNMT expression increased in CRS tissues. DNMT expression was positively correlated with Lund–McKay CT scores. TGF-β1 dose-dependently induced DNMT expression. Further, 5-Aza inhibited TGF-β1-induced DNMT, Snail, and Slug expression related to EMT, as well as p38 and JNK phosphorylation in A549 cells and TGF-β1-induced DNMT expression and EMT in primary nasal epithelial cells and air–liquid interface cultures. TGF-β1-induced DNMT expression leads to DNA methylation and EMT via p38, JNK, Snail, and Slug signaling pathways. Inhibition of DNMT suppressed the EMT process and therefore is potentially a CRS therapeutic strategy.

Highlights

  • IntroductionChronic rhinosinusitis (CRS), one of the most common chronic inflammatory diseases, is characterized by symptoms such as rhinorrhea, postnasal drip, nasal obstruction or congestion, sinus pain or pressure, and anosmia or hyposmia, lasting for at least 12 weeks [1]

  • Chronic rhinosinusitis (CRS), one of the most common chronic inflammatory diseases, is characterized by symptoms such as rhinorrhea, postnasal drip, nasal obstruction or congestion, sinus pain or pressure, and anosmia or hyposmia, lasting for at least 12 weeks [1].CRS is a multifactorial disease caused by environmental exposure factors, persistent viral infection, and genetic predisposition in its pathogenesis, which are suggested to cause different therapeutic responses [2]

  • CRS Was Associated with DNA Methylation and DNA methyltransferases (DNMTs) Expression

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Summary

Introduction

Chronic rhinosinusitis (CRS), one of the most common chronic inflammatory diseases, is characterized by symptoms such as rhinorrhea, postnasal drip, nasal obstruction or congestion, sinus pain or pressure, and anosmia or hyposmia, lasting for at least 12 weeks [1]. CRS is a multifactorial disease caused by environmental exposure factors, persistent viral infection, and genetic predisposition in its pathogenesis, which are suggested to cause different therapeutic responses [2]. The heterogeneous pathology of chronic sinonasal inflammation in CRS can be differentiated based on the distribution of inflammatory cells, histopathology, and remodeling processes [3]. There are limitations in the treatment of CRS based on phenotype. At least 10% of patients with CRS develop recurrent 4.0/). Refractory diseases that do not respond to medical and surgical treatment regimens. A new therapeutic approach to treat CRS is required

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