Regulation of inflammatory genes involved in periodontal diseases by DNA methylation

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  • June 7, 2019
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  • Zhang, Shaoping
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • Both bacterial infection and inflammatory immune responses by the host contribute to the pathogenesis of periodontal diseases, which include gingivitis in an early stage and periodontitis in a more advanced stage. DNA methylation, the most stable epigenetic modification, modulates gene expression without changing DNA sequences. The persistence of biofilm and the inflammation induced by periodontal pathogens may cause epigenetic modifications within the promoter region of genes in local tissues at the biofilm-gingival interface. We therefore hypothesize that DNA methylation is a regulatory mechanism for transcription of genes involved in both innate and adaptive immune responses in periodontal diseases. Using clinical gingival biopsies, we identified an overall increased methylation level within the prostaglandin-endoperodie synthase-2 (PTGS2) promoter region in tissues with chronic periodontitis. The methylation level at one locus, which is -458bp in the PTGS2 promoter region, is inversely related to the transcription of this gene. We also identified methylation changes of the tumor necrosis factor alpha (TNFA) promoter region specific to different stages of periodontal diseases in clinical biopsies. Transcription of TNFA is also inversely related to the methylation level at one locus, which is -163bp within the TNFA promoter. In addition, a hypomethylation profile within the interferon gamma (IFNG) promoter region is only present in samples exhibiting chronic periodontitis but not in induced gingivitis samples. In order to study whether Campylobacter rectus (C. rectus), a periodontal pathogen, is involved in the epigenetic regulation of inflammatory moleculs, we cultured THP.1 cells with C. recuts. An overall hypomethylation of CpG sites within the TNFA promoter and a progressive loss of methylation at -72bp locus are present in the THP-1 cells challenged by live C. rectus. In addition, the identified hypomethylation pattern is related to an increase of the transcriptional of TNFA. Using 5-aza-2deoxycytidine, a DNMT inhibitor, and a promoter-specific methylation luciferase reporter assay we confirmed that the methylation level of TNFA promoter negatively regulates the transcription of TNFA. The data from this study provide evidence to support that altered DNA methylation profile identified in the promoter regions of several inflammatory genes contributes to the transcriptional regulation of those genes in periodontal diseases.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Oral Biology.
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  • Offenbacher, Steven
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