Lal Devyani, Brar Tripti, McCabe Chantal, Jessen Erik, Kumar Nitish, Lança Gomes Pedro, Marino Michael J, Miglani Amar, Kita Hirohito
Department of Otolaryngology-Head & Neck Surgery, Mayo Clinic in Arizona, Phoenix, AZ, United States.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States.
Front Allergy. 2025 Jun 5;6:1606255. doi: 10.3389/falgy.2025.1606255. eCollection 2025.
OBJECTIVES/HYPOTHESIS: Chronic rhinosinusitis (CRS) may be triggered by environmental insults. We hypothesized that CRS results from epigenetic modifications of host DNA from external insults, leading to downstream RNA/DNA gene expression changes and immuno-mechanical disruptions. We therefore performed a multi-omics study integrating epigenetic (DNA methylation), transcriptomic (mRNA), and proteomic (cytokine) data of CRS sinonasal tissue to visualize interactions amongst these modalities to study our hypothesis.
Sinonasal tissue was collected from 14 prospectively enrolled CRS and control subjects. Cytokine, mRNA transcriptome, and DNA methylome analysis were performed. Multi-omics analysis via joint dimensional reduction (JDR) was conducted.
Multi-omics unsupervised clustering separated subjects into two distinct groups: one cluster of 9 CRS subjects and another with 3 controls and 2 non-eosinophilic CRSsNP subjects. DNA methylation, followed by mRNA expression, contributed most to cluster assignment. DNA methylation was the most significant data modality contributing to total variance on JDR. Cytokines critical in CRS (IL-5, IL-13, IL-10, IFN, IL-6) associated with hundreds of differentially methylated regions (DMRs) and mRNA. On conjoint analyses, common upstream DMRs and mRNAs were linked to cytokines IL-5 and IL-13, cytokines IL-10 and IFN, and cytokines IFN and IL-6, respectively.
Our results support the hypothesis that environmental insults may be significant drivers of CRS pathogenesis through epigenetic mechanisms that result in dysregulated mRNA transcription and cytokine expression. The most novel part of this study is our multi-omics approach that used integration of epigenetic (DNA methylation), transcriptomic (mRNA), and proteomic (cytokine) data to uncover insights into CRS pathogenesis; this is the first of its kind in CRS etiopathogenesis. The multi-omics analysis clearly separated clusters of control and CRS subjects, demonstrating its validity in future research. The study also identified interactions of methylated DNA, mRNA, and cytokines in CRS pathogenesis, highlighting novel molecules and pathways that may be potential therapeutic targets.
目的/假设：慢性鼻-鼻窦炎（CRS）可能由环境损伤引发。我们推测CRS是由外部损伤导致宿主DNA的表观遗传修饰引起的，进而导致下游RNA/DNA基因表达变化和免疫-机械功能紊乱。因此，我们进行了一项多组学研究，整合CRS鼻窦组织的表观遗传学（DNA甲基化）、转录组学（mRNA）和蛋白质组学（细胞因子）数据，以可视化这些模式之间的相互作用，从而研究我们的假设。
从14名前瞻性招募的CRS患者和对照受试者中收集鼻窦组织。进行细胞因子、mRNA转录组和DNA甲基化组分析。通过联合降维（JDR）进行多组学分析。
多组学无监督聚类将受试者分为两个不同的组：一组为9名CRS受试者，另一组为3名对照受试者和2名非嗜酸性CRS伴鼻息肉（CRSsNP）受试者。DNA甲基化，其次是mRNA表达，对聚类分配贡献最大。DNA甲基化是对JDR总方差贡献最大的显著数据模式。CRS中关键的细胞因子（IL-5、IL-13、IL-10、IFN、IL-6）与数百个差异甲基化区域（DMR）和mRNA相关。在联合分析中，常见的上游DMR和mRNA分别与细胞因子IL-5和IL-13、细胞因子IL-10和IFN以及细胞因子IFN和IL-6相关。
我们的结果支持以下假设，即环境损伤可能是CRS发病机制的重要驱动因素，其通过表观遗传机制导致mRNA转录和细胞因子表达失调。本研究中最新颖的部分是我们的多组学方法，该方法整合了表观遗传学（DNA甲基化）、转录组学（mRNA）和蛋白质组学（细胞因子）数据，以揭示CRS发病机制的见解；这在CRS病因发病学研究中尚属首次。多组学分析清楚地分离了对照和CRS受试者的聚类，证明了其在未来研究中的有效性。该研究还确定了甲基化DNA、mRNA和细胞因子在CRS发病机制中的相互作用，突出了可能成为潜在治疗靶点的新分子和途径。
