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Epigenetic regulation of inflammation in localized aggressive periodontitis.
Clin Epigenetics. 2017; 9:94.CE

Abstract

BACKGROUND

We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 μl (100 ng/μl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2).

RESULTS

Significant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients.

CONCLUSIONS

Our findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes.

TRIAL REGISTRATION

https://clinicaltrials.gov, NCT01330719.

Authors+Show Affiliations

Department of Periodontology, University of Florida College of Dentistry, P.O. Box 100434, Gainesville, FL 32610-0434 USA. Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL USA.Department of Periodontology, University of Florida College of Dentistry, P.O. Box 100434, Gainesville, FL 32610-0434 USA.Department of Periodontology, University of Florida College of Dentistry, P.O. Box 100434, Gainesville, FL 32610-0434 USA.Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL USA.Center for Pharmacogenomics, University of Florida, Gainesville, FL USA.Department of Periodontology, University of Florida College of Dentistry, P.O. Box 100434, Gainesville, FL 32610-0434 USA.

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28883894

Citation

Shaddox, L M., et al. "Epigenetic Regulation of Inflammation in Localized Aggressive Periodontitis." Clinical Epigenetics, vol. 9, 2017, p. 94.
Shaddox LM, Mullersman AF, Huang H, et al. Epigenetic regulation of inflammation in localized aggressive periodontitis. Clin Epigenetics. 2017;9:94.
Shaddox, L. M., Mullersman, A. F., Huang, H., Wallet, S. M., Langaee, T., & Aukhil, I. (2017). Epigenetic regulation of inflammation in localized aggressive periodontitis. Clinical Epigenetics, 9, 94. https://doi.org/10.1186/s13148-017-0385-8
Shaddox LM, et al. Epigenetic Regulation of Inflammation in Localized Aggressive Periodontitis. Clin Epigenetics. 2017;9:94. PubMed PMID: 28883894.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic regulation of inflammation in localized aggressive periodontitis. AU - Shaddox,L M, AU - Mullersman,A F, AU - Huang,H, AU - Wallet,S M, AU - Langaee,T, AU - Aukhil,I, Y1 - 2017/09/02/ PY - 2017/03/20/received PY - 2017/08/07/accepted PY - 2017/9/9/entrez PY - 2017/9/9/pubmed PY - 2018/5/22/medline KW - Aggressive periodontitis KW - Epigenetics KW - Inflammation KW - Leukotoxins KW - Toll-like receptors SP - 94 EP - 94 JF - Clinical epigenetics JO - Clin Epigenetics VL - 9 N2 - BACKGROUND: We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 μl (100 ng/μl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2). RESULTS: Significant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients. CONCLUSIONS: Our findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01330719. SN - 1868-7083 UR - https://www.unboundmedicine.com/medline/citation/28883894/Epigenetic_regulation_of_inflammation_in_localized_aggressive_periodontitis_ L2 - https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-017-0385-8 DB - PRIME DP - Unbound Medicine ER -