Vascular Disease
Dysregulation of DNA Methylation in the Aryl-Hydrocarbon Receptor Repressor (AHRR) Gene
2022 年 86 巻 6 号 p. 993-994
詳細
2022 年 86 巻 6 号 p. 993-994
DNA methylation usually occurs at the 5th position of the base cytosine to generate 5-methyl-cytosine (5mC), typically in the context of CpG dinucleotides.1 The distribution of DNA methylation genome-wide correlates with the transcriptional state, and is often used as a biomarker in development, aging, and disease.2 DNA methylation is established de novo by catalytic activity of the DNA methyltransferases DNMT3a, DNMT3b, and DNMT3c, and is maintained through cell division by DNMT1. By contrast, when transcription factors bind to the regulatory elements, they recruit TET enzymes, which oxidize 5mC to hydroxymethyl-cytosine (5hmC), formyl-cytosine (5fC), and carboxyl-cytosine (5caC), actively removing DNA methylation. Therefore, gene distal regulatory elements, such as enhancers, have highly variable levels of DNA methylation across individual cells and cell types.3
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Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide, but self-reported smoking information could include inaccuracies; therefore, an objective biomarker of smoking habits is needed. A recent epigenome-wide association study (EWAS) showed that smoking was associated with significant DNA demethylation at intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene (cg05575921).4 In this issue of the Journal, Takeuchi et al add more detailed evidence.5
Through an EWAS in a Japanese population, they not only validated the association between AHRR cg05575921 demethylation and smoking status, but also showed that smoking-related AHRR cg05575921 hypomethylation remains for a long period of time, 20 years or more, even after smoking cessation.5 They also reveal that AHRR cg05575921 hypomethylation appears to become evident from a relatively early stage of smoking (i.e., <10 years) among current smokers. These results suggest that AHRR cg05575921 hypomethylation is a quantifiable marker of smoking habits, including early stage or cessation stage of smoking. Takeuchi et al further show an inverse correlation between the AHRR cg05575921 methylation extent and AHRR mRNA expression, suggesting a functional role of AHRR cg05575921 as an enhancer of AHRR (Figure).
Mechanistic model showing that smoking- or PTSD-related activation of AhR signaling promotes inflammation and accelerates the development of cardiovascular diseases via DNA hypomethylation of AHRR. PTSD, post-traumatic stress disorder.
AHRR is one of the genetic targets of the aryl-hydrocarbon receptor (AhR) pathway. In lymphocytes, monocytes and dendritic cells, when a ligand binds to the cytosolic AhR, it translocates to the nucleus, where it drives expression of its target genes, including AHRR, and induces several immune responses.6 Therefore, high expression of AHRR indicates activation of the AhR signaling pathway. AhR ligands, such as dioxin or polycyclic aromatic hydrocarbons, in cigarette smoke, tend to promote differentiation into Th17 and expression of pro-inflammatory cytokines.7 A recent transcriptome-wide association study showed that expression levels of AHRR are associated with a genetic predisposition to clonal hematopoiesis of indeterminate potential,8 which is consistent with the finding that AhR signaling pathway directs hematopoietic progenitor cell expansion and differentiation.9AHRR cg05575921 hypomethylation has also been shown to be associated with post-traumatic stress disorder,10 which is involved in increased inflammatory cytokines11 and susceptibility to cardiovascular disease.12
In conclusion, AHRR cg05575921 hypomethylation suggests smoking- or PTSD-related activation of AhR signaling in immune cells. Considering the possibility that subsequent activation of inflammatory cytokines accelerates the development of cardiovascular diseases,13 modulation of this signaling is expected to be a therapeutic strategy in the cardiovascular field.
H.M. is a member of Circulation Journal’s Editorial Board.
