Abstract
BackgroundIn 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.Methods and resultsGenome-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.ConclusionsOur results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.
Highlights
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 inflam‐ mation
By applying our recently published “intercept-method” for the inference of effect sizes adjusted for confounding factors [16] to our data, we provide adapted estimations of the effect sizes at differentially methylated positions (DMPs), which allows us to shed light on the molecular mechanisms altered in the etiology of periodontitis
Pre‐processing pipeline 786,547 probes passed the quality control (QC) criteria and were analyzed in ex vivo gingival tissue biopsies from 60 periodontitis patients obtained from an inflamed and an uninflamed site each
Summary
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 inflam‐ mation. Richter et al Clin Epigenet (2021) 13:203 is the most common modification of DNA that occurs at CpG dinucleotides (cytosine followed by guanine) It typically causes chromatin condensation and disruption of interactions between DNA and transcription factors, which are associated with transcriptional regulation [5]. Such epigenetic modifications of the chromatin confer plasticity to the genome and enable flexible and reversible responses of the genetic information to environmental challenges, allowing long-term adaptation and fine-tuning of gene expression levels [6]. It is considered that the development of adverse immune reactions may be associated with these challenges
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