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A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers

Please always quote using this URN: urn:nbn:de:bvb:20-opus-226175
  • Background The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivoBackground The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. Conclusion This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.show moreshow less

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Metadaten
Author: Gesa M. Richter, Jochen Kruppa, Matthias Munz, Ricarda Wiehe, Robert Häsler, Andre Franke, Orlando Martins, Yvonne Jockel-Schneider, Corinna Bruckmann, Henrik Dommisch, Arne S. Schaefer
URN:urn:nbn:de:bvb:20-opus-226175
Document Type:Journal article
Faculties:Medizinische Fakultät / Poliklinik für Zahnerhaltung und Parodontologie
Language:English
Parent Title (English):Clinical Epigenetics
Year of Completion:2019
Volume:11
Article Number:105
Pagenumber:1-18
Source:Clinical Epigenetics (2019) 11:105
DOI:https://doi.org/10.1186/s13148-019-0697-y
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
GND Keyword:AHRR; Cytochrome P 450 pathway; OSCC; Smoking
Tag:CYP1B1; EWAS; Expression; Masticatory mucosa; Methylation
Release Date:2021/08/10
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International