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1.
J Dent Res ; 102(13): 1468-1477, 2023 12.
Article in English | MEDLINE | ID: mdl-37800405

ABSTRACT

Periodontitis is a multifactorial disease that progresses via dynamic interaction between bacterial and host-derived genetic factors. The recent trend of omics analyses has discovered many periodontitis-related risk factors. However, how much the individual factor affects the pathogenesis of periodontitis is still unknown. This article aims to identify multiple key factors related to the pathogenesis of periodontitis and quantitatively predict the influence of each factor on alveolar bone resorption by omics analysis and mathematical modeling. First, we induced periodontitis in mice (n = 3 or 4 at each time point) by tooth ligation. Next, we assessed alveolar bone resorption by micro-computed tomography, alterations in the gene expression by RNA sequencing, and the microbiome of the gingivae by 16S ribosomal RNA sequencing during disease pathogenesis. Omics data analysis identified key players (bacteria and molecules) involved in the pathogenesis of periodontitis. We then constructed a mathematical model of the pathogenesis of periodontitis by employing ordinary differential equations that described the dynamic regulatory interplay between the key players and predicted the alveolar bone integrity as output. Finally, we estimated the model parameters using our dynamic experimental data and validated the model prediction of influence on alveolar bone resorption by in vivo experiments. The model predictions and experimental results revealed that monocyte recruitment induced by bacteria-mediated Toll-like receptor activation was the principal reaction regulating alveolar bone resorption in a periodontitis condition. On the other hand, osteoblast-mediated osteoclast differentiation had less impact on bone integrity in a periodontitis condition.


Subject(s)
Alveolar Bone Loss , Periodontitis , Mice , Animals , X-Ray Microtomography/adverse effects , Disease Models, Animal , Alveolar Bone Loss/metabolism , Osteoclasts/metabolism , Periodontitis/microbiology
2.
Oncogene ; 27(54): 6817-33, 2008 Nov 20.
Article in English | MEDLINE | ID: mdl-18762811

ABSTRACT

Hypomethylation of repeated elements in the genome is a common feature of human cancer, however, the direct consequences of this epigenetic defect for cancer biology are still largely unknown. Telomeres are specialized chromatin structures at the ends of eukaryotic chromosomes formed by tandem repeats of G-rich sequences and associated proteins, which have an essential role in chromosome end protection and genomic stability. Telomeric DNA repeats cannot be methylated, however, the adjacent subtelomeric DNA is heavily methylated in humans. Here, we show that the methylation status of subtelomeric DNA repeats negatively correlates with telomere length and telomere recombination in a large panel of human cancer cell lines. These findings suggest that tumor telomere length and integrity can be influenced by epigenetic factors. Finally, we show that treatment of human cancer cell lines with demethylating drugs results in hypomethylation of subtelomeric repeats and increased telomere recombination, which in turn may facilitate telomere elongation. All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells.


Subject(s)
Epigenesis, Genetic/genetics , Gene Expression Regulation, Neoplastic , Neoplasms/genetics , Telomere/genetics , Acetylation , Cell Line, Tumor , DNA Methylation/genetics , DNA, Neoplasm/genetics , Gene Amplification , Genome, Human , Histones/genetics , Humans , Recombination, Genetic , Repetitive Sequences, Nucleic Acid/genetics , Telomerase/genetics , Telomerase/metabolism , Telomere/chemistry , Telomere/ultrastructure
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