Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

Abstract

The packaging of DNA around nucleosomes exerts dynamic control over eukaryotic gene expression either by granting access to the transcriptional machinery in an open chromatin state or by silencing transcription via chromatin compaction. Histone methylation modification affects chromatin through the addition of methyl groups to lysine or arginine residues of histones H3 and H4 by means of histone methyl transferases or histone demethylases. Changes in histone methylation state modulate periodontal gene expression and have profound effects on periodontal development, health, and therapy. At the onset of periodontal development, progenitor cell populations such as dental follicle cells are characterized by an open H3K4me3 chromatin mark on RUNX2, MSX2, and DLX5 gene promoters. During further development, periodontal progenitor differentiation undergoes a global switch from the H3K4me3 active methyl mark to the H3K27me3 repressive mark. When compared with dental pulp cells, periodontal neural crest lineage differentiation is characterized by repressive H3K9me3 and H3K27me3 marks on typical dentinogenesis-related genes. Inflammatory conditions as they occur during periodontal disease result in unique histone methylation signatures in affected cell populations, including repressive H3K9me3 and H3K27me3 histone marks on extracellular matrix gene promoters and active H3K4me3 marks on interleukin, defensin, and chemokine gene promoters, facilitating a rapid inflammatory response to microbial pathogens. The inflammation-induced repression of chromatin on extracellular matrix gene promoters presents a therapeutic opportunity for the application of histone methylation inhibitors capable of inhibiting suppressive trimethylation marks. Furthermore, inhibition of chromatin coregulators through interference with key inflammatory mediators such as NF-kB by means of methyltransferase inhibitors provides another avenue to halt the exacerbation of the inflammatory response in periodontal tissues. In conclusion, histone methylation dynamics play an intricate role in the fine-tuning of chromatin states during periodontal development and harbor yet-to-be-realized potential for the treatment of periodontal disease.

Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential

“…These changes favor a transcriptional program that suppresses PDL osteogenic differentiation [ 40 ]. In line with observations in isolated cell populations, unique histone methylation signatures have been observed in experimental periodontitis in mice [ 41 ]. Among them, the repressive H3K27Me3 mark appears to be most dynamically regulated under inflammatory conditions.…”

“…Among them, the repressive H3K27Me3 mark appears to be most dynamically regulated under inflammatory conditions. H3K27 trimethylation is enriched on the promoters of genes involved in extracellular matrix (ECM) turnover and reduced on cytokine, chemokine, and defensin gene promoters in samples from periodontitis-affected mice [ 41 ]. However, changes in histone methylation marks on the promoters of genes regulating early signaling events that are critical for Toll-like receptor (TLR)- and cytokine-induced responses have not been evaluated in the context of periodontal inflammation.…”

“…Although the key roles of histone methylation, in particular H3K4Me3 and H3K27Me3 marks, have been characterized in cellular and animal models of periodontitis [ 41 ], the therapeutic potential of compounds that modulate this process has not been evaluated. Gene silencing studies demonstrated that manipulation of enzymes that regulate histone methylation can suppress inflammatory activation and modulate the ability of PDL cells to differentiate into osteoblasts.…”

A Review of Antimicrobial Activity of Dental Mesenchymal Stromal Cells: Is There Any Potential?

“…Moreover, hPDLSCs-derived hBDs inhibited P. gingivalis growth [38]. hPDLCs also express defensin alpha 4, which is upregulated by LPS and regulated by epigenetic mechanisms [39,40].…”

Deciphering the Epigenetic Code of Stem Cells Derived From Dental Tissues

“…Histone 3 lysine 9 (H3K9) and H3K27 are associated with specific and dynamic repression of transcriptional regulation. By contrast, H3K4, H3K36, and H3K79 facilitate target gene transcriptional activation (32). Histone lysine demethylases (KDMs), removing methyl groups from histones, mainly include the lysine-specific demethylase 1 (LSD1) and Jumonji C (JMJC) families (33).…”