NIDCR Individual Predoctoral Scientist Fellowship

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DESCRIPTION (provided by applicant): Chronic inflammatory diseases such as periodontal disease are greatly exacerbated in diabetic patients (Wang and Kaltenboeck, 2010). The mechanism of the acceleration of periodontitis remains unknown, however, diabetes and periodontitis both activate the pro-inflammatory transcription factor NF-?B. Upon stimulation, NF-?B recruits other proteins such as modification enzymes. Modification enzymes alter the chromatin structure via histone modification mechanisms ultimately regulating transcription. In the present study, we will examine histone methylation of gene promoters concomitantly expressed in high glucose conditions (diabetes) and under lipopolysaccharide (LPS) challenge (periodontitis). Microarray gene expression analysis from our preliminary study revealed that periopathic LPS challenge affects three groups of NF-kB target genes corresponding to unique histone methylation signature: (i) immediate-early response genes associated with cell recruitment such as CCL2, CXCL1,and IL-6 which demonstrated active H3K4me3 methylation (ii) late response genes associated with cell activation and defense mechanisms such as IL-1ß, TNF-α, and several defensins that featured repressive H3K9me3 and/or H3K27me3 methylation and (iii) matrix-related genes involved in bone and connective tissue metabolism such as collagens I and III, MMP2 and 9, and RANKL were occupied by both active and repressive trimethylation marks. We propose that long-term inflammation severely alters the methylation state of these periodontal connective tissues which diminishes its ability to function normally and results in chronic periodontitis. We thus hypothesize that in response to periopathic LPS challenge and high glucose conditions, NF-kB avails itself of the histone methylation machinery, resulting in upregulation of pro-inflammatory genes and dysregulation of matrix-related genes, linked to exacerbated periodontitis under diabetic conditions. We have therefore developed a research plan to (1) identify gene expression and epigenetic histone methylation patterns in the aforementioned groups of NF-kB target genes during the progression of periodontitis, (2) to determine the role of NF-κB and chromatin modifications in the exacerbated periodontal phenotype of diabetic animals, and (3) identify the relationship between NF-κB signaling, chromatin structure and histone methylation. Together, these experiments will provide epigenetic information about functional links between diabetes and periodontitis which may result in improvements in therapeutic strategies for periodontitis under diabetic conditions.