SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation.

Area of Science:

• Molecular Biology
• Immunology
• Periodontology

Background:

• Inflammatory responses in periodontal disease are regulated by chromatin modifications on inflammatory gene promoters.
• The methyltransferase SETD1B's role in histone H3 lysine K4 (H3K4) trimethylation of these promoters is not fully understood.

Purpose of the Study:

• To investigate the function of SETD1B in histone methylation and inflammatory gene expression in periodontal ligament cells.
• To determine the relationship between SETD1 and nuclear factor-κB (NF-κB) activation using the inhibitor BOT-64.
• To evaluate BOT-64's efficacy in reversing inflammatory tissue destruction in a mouse periodontitis model.

Main Methods:

• In vitro study using periodontal ligament (PDL) cells treated with *Porphyromonas gingivalis* lipopolysaccharide (LPS).
• Subcutaneous implantation model to assess SETD1 and NF-κB interactions with BOT-64.
• In vivo mouse periodontitis model to test BOT-64's therapeutic effects.

Main Results:

• *P. gingivalis* LPS increased H3K4me3 on IL-1β, IL-6, and MMP2 gene promoters in PDL cells.
• SETD1B inhibition reduced H3K4me3 and inflammatory gene expression in LPS-treated cells.
• LPS increased SETD1 nuclear localization and NF-κB (p65) translocation, indicating a synergistic effect.
• BOT-64 treatment reduced SETD1-positive cells, restored tissue integrity, and enhanced osteogenesis in vivo.

Conclusions:

• SETD1 is crucial for chromatin relaxation at inflammatory gene promoters via H3K4 trimethylation, driving periodontal inflammation.
• BOT-64 effectively inhibits NF-κB activity and ameliorates SETD1-induced chromatin relaxation, offering a therapeutic strategy for periodontal disease.