Histone Methylation Mechanisms in Periodontal Disease and Regeneration

Periodontitis is a common oral disease and is one of the major reasons for tooth loss in the United States. The consequences of severe periodontitis include increased tooth mobility and ultimately tooth loss. The pathogenesis pathway of periodontitis leads to activation of the pro-inflammatory transcription factor NF-kB. Activation of NF-kB signaling results in the synthesis and secretion of a wide array of pro-inflammatory mediators, including cytokines (IL-1, IL-6, TNF-α) and chemokines (CC and CXC). Upon stimulation, NF-kB translocates into the nucleus and participates in chromatin dynamics, including histone remodeling and histone modification. The mechanism of NF-kB activation may involve recruitment of modification enzymes (e.g. acetylases, methylases) that alter the chromatin structure via histone modification mechanisms (e.g. acetylation, phosphorylation and methylation), ultimately regulating transcription. Previous studies have demonstrated that NF-kB mediated inflammatory gene expression induced by pro-inflammatory signals is associated with changes in histone methylation state in vascular cells and monocytes. Histone lysine methylation stands out as a relatively reversible chromatin modification and as a prime candidate mechanism responsible for the response of periodontal cells and tissues to dental plaque biofilm in periodontitis patients. We propose that during long-term exposure to NF-kB activation, the histone methylation state of the periodontal connective tissues is severely altered which diminishes its ability to function physiologically, to heal, and to regenerate. Development of gene specific modulators targeting NF-kB signaling and unique histone lysine methylation pathways will allow us to combat the connective tissue breakdown that occurs as a result of the inflammatory component of periodontal disease.