Decoding Epigenetic Regulation in Periodontal Disease

Periodontal disease is a chronic inflammatory condition initiated by dysbiotic microbial biofilms and sustained by a dysregulated host response that culminates in connective tissue destruction and alveolar bone loss. While microbial challenge and classical risk factors such as smoking, diabetes, and aging shape disease susceptibility and severity, they do not fully explain the heterogeneity in clinical presentation, progression rates, or treatment responsiveness. Epigenetic regulation provides a biologically plausible bridge between environmental exposures and durable, context-dependent changes in gene expression in periodontal tissues. This review synthesizes contemporary evidence on the epigenetic architecture of periodontal disease, focusing on DNA methylation and demethylation dynamics, histone modifications and chromatin reader mechanisms, non-coding RNA networks, and emerging epitranscriptomic processes such as N6-methyladenosine RNA modification. We discuss how these layers influence inflammatory signaling, innate and adaptive immune crosstalk, osteoclastogenesis, extracellular matrix remodeling, and resolution pathways, and how periodontal pathogens can modulate host epigenetic machinery. Finally, we evaluate translational opportunities for epigenetic biomarkers in saliva, gingival crevicular fluid, gingival tissue, and blood, and the potential of host-modulation strategies targeting histone deacetylases and bromodomain proteins, while emphasizing methodological considerations, causal inference challenges, and priorities for multi-omics and longitudinal studies. Translational opportunities are strongest in biomarker development and adjunctive host modulation targeting histone acetylation pathways, provided that future research improves cellular resolution, standardization, longitudinal validation, and causal interpretation.