AbstractsBiology & Animal Science

Gene expression profiling in periodontitis

by Haleh Davanian Mohaghegh




Institution: Karolinska Institute
Department:
Year: 2015
Record ID: 1343398
Full text PDF: http://hdl.handle.net/10616/44495


Abstract

The chronic inflammatory disease periodontitis is characterized by destruction of periodontal tissue, i.e. the tissues that surround and support the teeth. This complex disease is multifactorial, involving oral pathogens, an unfavorable host inflammatory response, environmental and genetic factors, as well as an altered gene expression contributing to disease pathology. Despite extensive research of excellent quality, the genes involved in periodontitis remain uncharacterized and the mechanisms responsible for the destruction of periodontal tissue are poorly understood. Here, in attempt to gain further insight into and identify biomarkers for this disease, we have characterized global gene expression in periodontitis-affected gingival tissue and gingival fibroblasts. Initially, we employed microarrays to examine gene expression in gingival fibroblasts, the predominant cell type in gingival connective tissue, after evoking an inflammatory response in these cells with tumor necrosis factor-α (TNF-α). This inflammatory mediator up-regulated the expression of a wide range of genes and, furthermore, activated several signaling pathways involved in immune and inflammatory responses, in particular the toll-like receptor (TLR) signaling pathway. We subsequently confirmed for the first time that TNF-α-enhances the expression of TLR2 in gingival fibroblasts at both the mRNA and protein levels. In addition, we found that the c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NFkB) signal transduction pathways, as well as prostaglandin 15d-PGJ2, which has been proposed to be anti-inflammatory, are involved in this up-regulation. Next, we examined the transcriptome, employing RNA-sequencing, in periodontitis-affected and healthy gingival tissue from patients with periodontitis. We demonstrated, as expected, that the degree of inflammation in periodontitis-affected gingival tissue is more pronounced than in corresponding healthy tissue from the same individual. Cluster analysis revealed that the clustering depended on the degree of inflammation, rather than the individual from whom the tissue was taken, indicating the existence of a characteristic gene expression profile for periodontitis. In addition, we identified two novel genes, interferon regulatory factor 4 (IRF4) and Chemokine (C-C motif) ligand 18 (CCL18) that were up-regulated in association with periodontitis. In our third study, we utilized the RNA-sequencing approach to characterize gene expression in a large number of gingival biopsies both from patients with periodontitis and healthy control subjects. Among the several genes that were significantly up- or down-regulated in periodontitis, the two most differentially expressed were mucin 4 (MUC4) and matrix metalloproteinase 7 (MMP7). This investigation provides a comprehensive map of the gene expression associated with periodontitis and, suggests that MUC4 and MMP7 might be potentially valuable biomarkers and clinical therapeutic targets for periodontitis. In conclusion, the information we…