Department of Periodontology and Synoptic Dentistry, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Aßmannshauser Str. 4-6, 14197, Berlin, Germany.
Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
Clin Epigenetics. 2021 Nov 3;13(1):203. doi: 10.1186/s13148-021-01190-7.
In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis.
Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed "intercept-method". In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response (CCL26, DNAJC1, BPI). Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets.
Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.
在黏膜屏障界面中，基因表达对长期环境变化的灵活响应允许适应和微调宿主防御和失控的未解决炎症之间的平衡。染色质的表观遗传修饰赋予遗传信息的可塑性，并深入了解组织如何利用遗传信息来适应环境因素。口腔黏膜特别容易受到环境应激源的影响，例如可变的微生物群。同样，持续的口腔炎症是口腔炎症性疾病牙周炎的最重要内在危险因素，并且具有改变 DNA 甲基化模式的强大潜力。本研究的目的是确定长期炎症反应导致牙周炎时口腔咀嚼黏膜的表观遗传变化。
使用 Infinium MethylationEPIC BeadChip 分析了 60 例牙周炎病例的炎症和临床无炎症的固体牙龈组织活检的全基因组 CpG 甲基化。我们使用 EpiDish 算法验证并对浸润免疫细胞进行了细胞类型去卷积。使用我们最近开发的“截距法”，估计了牙龈上皮和成纤维细胞中 DMP 的效应大小，并针对混杂因素进行了调整。在当前的 EWAS 中，我们确定了各种在牙周炎患者的牙周炎炎症和非炎症口腔黏膜之间表现出明显不同甲基化的基因。ROBO2、PTP4A3 等在伤口愈合中起作用的基因、LPXN 等细胞黏附基因以及 CCL26、DNAJC1、BPI 等固有免疫反应基因的差异最为明显。富集分析表明，表观遗传变化在囊泡转运基因集中起作用。
我们的结果表明，口腔黏膜对持续炎症环境的特定适应涉及伤口修复、屏障完整性和先天免疫防御。
