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

Abstract

Background Epigenetics studies mechanisms such as DNA methylation, histone modifications, non-coding RNAs, and alternative polyadenylation that can modify gene activity without changing the underlying DNA nucleotide base-pair structure. Because these changes are reversible, they have potential in developing novel therapeutics. Currently, seven pharmaceutical agents targeting epigenetic changes are FDA approved and commercially available for treatment of certain cancers. However, studies investigating epigenetics in chronic rhinosinusitis (CRS) have not been undertaken previously in the United States. Objectives The goal of this study was to investigate sinonasal DNA methylation patterns in CRS versus controls, to discern environmentally-induced epigenetic changes impacting CRS subjects. Methods and Results Ethmoidal samples from CRS and inferior turbinate mucosal tissue samples from controls without CRS were studied. DNA methylation was studied by Reduced Representation Bisulfite Sequencing. RADMeth® biostatistical package was used to identify differentially methylated regions (DMRs) between CRS and controls. Ingenuity Pathway analysis of DMRs was performed to identify top upstream regulators and canonical pathways. Ninety-three samples from 64 CRS subjects (36 CRSwNP; 28 CRSsNP) and 29 controls were studied. CRS and control samples differed in 13 662 CpGs sites and 1381 DMRs. Top upstream regulators identified included: 1. CRS versus controls: TGFB1, TNF, TP53, DGCR8, and beta-estradiol. 2. CRSwNP versus controls: TGFB1, CTNNB1, lipopolysaccharide, ID2, and TCF7L2. 3. CRSsNP versus controls: MYOD1, acetone, ID2, ST8SIA4, and LEPR. Conclusions Differential patterns of methylation were identified between controls and CRS, CRSwNP, and CRSsNP. Epigenetic, environmentally-induced changes related to novel, inflammatory, immunologic, and remodeling pathways appear to affect epithelial integrity, cell proliferation, homeostasis, vascular permeability, and other yet uncharacterized pathways and genes.

Genomewide epigenetic study shows significant DNA hypermethylation in chronic rhinosinusitis versus control ethmoidal tissue

“…Previous genetic and epigenetic studies have implicated TNF alpha, showing higher levels in CRSwNP 9 . Other top URs include LPS (pro‐inflammatory toxin on the outer membrane of gram‐negative bacteria, activates TLR4 inflammation) and beta‐estradiol (a sex hormone) both of which were identified in our previous study 2 . Overall, the results greatly overlap with our previous DNA methylation study which used ITM for control 2 …”

“…TNF was another top UR in CRS/CRSwNP versus controls 2 . Previous genetic and epigenetic studies have implicated TNF alpha, showing higher levels in CRSwNP 9 .…”

“…In our previous study, comparing inferior turbinate mucosa (ITM) of controls with ethmoidal tissue (ET) of CRS subjects, we found methylation differences in inflammatory, immunologic, and remodeling pathways 2 . Other DNA methylation studies come from outside the United States, and also used ITM or uncinate process or “nasal mucosa tissue” as control tissue 3,4 .…”

“You are Always a Student, Never a Master: You Have to Keep Moving Forward” Conrad Hall

“…As research uncovers more about the nuances of Chronic Rhinosinusitis (CRS), more questions inevitably arise, and with that multitudes of opportunities for potential novel treatments. One such attempt to do so was undertaken by Brar et al 1 to understand and delineate the effects of epigenetics and environmentally induced pathogenic changes and its impact on CRS patients. In this study, several upstream regulators and pathways were identified as potential targets for CRS treatment.…”