At the 2023 American Rhinologic Society, Combined Otolaryngology Spring Meeting (ARS-COSM) in Boston, Massachusetts (May 4-5), a team of researchers from Mayo Clinic in Arizona, presented a study that aimed to perform the first genome-wide DNA methylation study comparing ethmoidal tissues of patients with chronic rhinosinusitis (CRS) versus controls to understand better the epigenetic mechanisms involved in gene expression influenced by the environment.
Research has shown that the environment greatly influences gene expression in CRS through epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs. DNA methylation reduces gene expression by inhibiting specific DNA sites that prevent the binding of transcription factors on the DNA.
Histone modifications control gene transcription by regulating the winding and unwinding of DNA, making the tightly coiled DNA around histones unable to undergo transcription. Chemical modifications, including acetylation and deacetylation, can change the amount of DNA available for transcription, with the earlier causing transcriptional activation and the later causing transcriptional repression.
Non-coding RNAs, including micro-RNAs (miRNAs) and long non-coding RNA (lncRNA), in addition to transcription, can control post-transcription protein synthesis, with miRNAs binding to target mRNAs causing their degradation while lncRNAs influence the methylation pattern of downstream genes. Therefore, the environment (microbes, allergens, pollutants, smoke, etc.) can induce changes in the “epigenome” through various mechanisms, ultimately affecting gene expression without disturbing the “genome.”
While epigenetic changes occur due to interaction between the host and environment, they can be passed on to offspring due to the pharmacogenetically reversible nature of these changes. A huge potential exists in developing biomarkers, novel treatments, and optimizing personalized therapeutics.
The study included patients classified into controls, CRS, and CRS phenotypes (CRSwNP, CRSsNP). Ethmoidal tissue samples were obtained during surgery, and reduced representation bisulfite sequencing (RRBS) was used to extract DNA for analysis.
The researchers identified significant hypermethylation in ethmoidal tissue in CRS compared to the controls. Moreover, it was observed that the epithelial-mesenchymal transition pathway, Th1 and Th2 activation pathways, and others might be epigenetically dysregulated in CRS.
Additionally, it was confirmed that the epigenetic changes are heritable and can be shared amongst family members. Moreover, the clustering of DMRs indicated that CRS continues to show relative hypermethylation across most DMRs compared to controls at various ranges of the methylation spectrum. Furthermore, TGFB1, TNF, and Lipopolysaccharide were found to be the top upstream regulators in all cohorts.
The authors claimed that their study findings are consistent with previous research using inferior turbinate tissue in controls and that their study is the first comprehensive genome-wide study of DNA methylation of ethmoidal tissue in CRS versus controls.
“The pathways identified in this study could be further studied for their involvement in CRS and their potential as drug targets, ” the authors concluded.
The study’s contributors include Tripti Brar, M.B.B.S, MD; Saurabh Baheti, M.S; Aditya Vijay Bhagwate, M.S; Michael J. Marino, MD; Hirohito Kita, MD; and Devyani Lal MD from Mayo Clinic Arizona, USA.
Reference:
Brar T, Baheti S, Bhagwate A, et al. Genome-wide Epigenetic Study Shows Significant DNA Hypermethylation in Ethmoidal Tissue of Chronic Rhinosinusitis versus Controls. ARS-COSM. May 4-5, 2023.