Tissue-specific moderate DNA methylation alterations featuring hypomethylation in microRNA regulatory regions associated with advanced carotid atherosclerosis
- 1Research Institute of Medical Genetics, Tomsk National Research Medical Center , ,
- 2Cardiology Research Institute, Tomsk National Research Medical Center , ,
Abstract
Introduction: DNA methylation is an important epigenetic mechanism involved in the regulation of gene expression, but its contribution to the regulation of microRNA genes in atherosclerosis remains poorly understood.
Methods: We profiled DNA methylation of regulatory elements and gene bodies of five microRNA genes (MIR10B, MIR21, MIR100, MIR127, and MIR143) in vascular tissues and paired peripheral blood leukocytes from 92 patients with advanced carotid atherosclerosis along with peripheral blood leukocytes of 32 subclinical atherosclerosis controls, using targeted bisulfite sequencing.
Results: We identified distinct tissue-specific DNA methylation patterns for all studied regions of microRNA genes. The regulatory regions of MIR10B, MIR127, and MIR100 were moderately hypomethylated in carotid atherosclerotic plaques compared with intact vascular tissues. We further integrated our findings with lab-internal and publicly available epigenome-wide methylation datasets and evaluated the contribution of vascular and blood cell composition using computational deconvolution. After adjustment for estimated vascular cell proportions, methylation at CpG sites within the MIR100 and MIR127 regions remained associated with atherosclerosis. Increased DNA methylation at a single CpG site (chr11:122025143, GRCh37/hg19) located in the MIR100 E-box region was associated with metabolic syndrome, while DNA methylation levels of MIR10B, MIR21, and MIR127 in atherosclerotic plaques were linked with indicators of histological instability and a history of acute cerebrovascular events. In peripheral blood cells, we observed moderate hypomethylation, predominantly at individual CpG sites within the regulatory regions of MIR10B, MIR21, and the MIR100 E-box region in patients compared with controls. However, MIR10B methylation showed weak associations with estimated blood cell composition. In blood, MIR10B and MIR143 methylation correlated with lipid metabolism and carotid stenosis, while the MIR21 CpG island showed strong correspondence between blood and plaque methylation. Using miRNA-seq to analyze microRNA expression in vascular samples, we identified miR-143–3p, miR-21–5p, miR-100–5p, miR-145–5p, miR-145–3p, and miR-10b-5p as the most highly expressed microRNAs. Methylation of CpG sites within MIR10B and MIR143HG (CARMN) promoters was inversely associated with the expression of the corresponding microRNAs.
Discussion: Advanced carotid atherosclerosis is characterized by specific moderate tissue-associated DNA methylation patterns of microRNA genes, predominantly involving hypomethylation of regulatory regions. These epigenetic shifts, driven both by changes in vascular cell composition and the functional state of the vessel wall, enable highly coordinated regulation of microRNA expression profiles. These findings highlight promising candidate loci and biomarkers for predicting the complicated course of atherosclerosis, which warrants further validation in larger independent cohorts.
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BibTeX
@article{koroleva2026tissuespecific,
title = {{Tissue-specific moderate DNA methylation alterations featuring hypomethylation in microRNA regulatory regions associated with advanced carotid atherosclerosis}},
author = {Iuliia A. Koroleva and Alexey A. Zarubin and Anton V. Markov and Alexey A. Sleptcov and Mikhail S. Kuznetsov and Boris N. Kozlov and Elvira F. Muslimova and Sergey A. Afanasiev and Nadezhda P. Babushkina and Elena Yu. Bragina and Irina A. Goncharova and Maria V. Golubenko and Aksana N. Kucher and Maria S. Nazarenko},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1948449},
url = {https://europepmc.org/article/PMC/PMC13724618},
note = {CC BY},
}
RIS
TY - JOUR
TI - Tissue-specific moderate DNA methylation alterations featuring hypomethylation in microRNA regulatory regions associated with advanced carotid atherosclerosis
AU - Iuliia A. Koroleva
AU - Alexey A. Zarubin
AU - Anton V. Markov
AU - Alexey A. Sleptcov
AU - Mikhail S. Kuznetsov
AU - Boris N. Kozlov
AU - Elvira F. Muslimova
AU - Sergey A. Afanasiev
AU - Nadezhda P. Babushkina
AU - Elena Yu. Bragina
AU - Irina A. Goncharova
AU - Maria V. Golubenko
AU - Aksana N. Kucher
AU - Maria S. Nazarenko
PY - 2026
DA - 2026/10/19
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1948449
UR - https://europepmc.org/article/PMC/PMC13724618
AB - Introduction: DNA methylation is an important epigenetic mechanism involved in the regulation of gene expression, but its contribution to the regulation of microRNA genes in atherosclerosis remains poorly understood. Methods: We profiled DNA methylation of regulatory elements and gene bodies of five microRNA genes (MIR10B, MIR21, MIR100, MIR127, and MIR143) in vascular tissues and paired peripheral blood leukocytes from 92 patients with advanced carotid atherosclerosis along with peripheral blood leukocytes of 32 subclinical atherosclerosis controls, using targeted bisulfite sequencing. Results: We identified distinct tissue-specific DNA methylation patterns for all studied regions of microRNA genes. The regulatory regions of MIR10B, MIR127, and MIR100 were moderately hypomethylated in carotid atherosclerotic plaques compared with intact vascular tissues. We further integrated our findings with lab-internal and publicly available epigenome-wide methylation datasets and evaluated the contribution of vascular and blood cell composition using computational deconvolution. After adjustment for estimated vascular cell proportions, methylation at CpG sites within the MIR100 and MIR127 regions remained associated with atherosclerosis. Increased DNA methylation at a single CpG site (chr11:122025143, GRCh37/hg19) located in the MIR100 E-box region was associated with metabolic syndrome, while DNA methylation levels of MIR10B, MIR21, and MIR127 in atherosclerotic plaques were linked with indicators of histological instability and a history of acute cerebrovascular events. In peripheral blood cells, we observed moderate hypomethylation, predominantly at individual CpG sites within the regulatory regions of MIR10B, MIR21, and the MIR100 E-box region in patients compared with controls. However, MIR10B methylation showed weak associations with estimated blood cell composition. In blood, MIR10B and MIR143 methylation correlated with lipid metabolism and carotid stenosis, while the MIR21 CpG island showed strong correspondence between blood and plaque methylation. Using miRNA-seq to analyze microRNA expression in vascular samples, we identified miR-143–3p, miR-21–5p, miR-100–5p, miR-145–5p, miR-145–3p, and miR-10b-5p as the most highly expressed microRNAs. Methylation of CpG sites within MIR10B and MIR143HG (CARMN) promoters was inversely associated with the expression of the corresponding microRNAs. Discussion: Advanced carotid atherosclerosis is characterized by specific moderate tissue-associated DNA methylation patterns of microRNA genes, predominantly involving hypomethylation of regulatory regions. These epigenetic shifts, driven both by changes in vascular cell composition and the functional state of the vessel wall, enable highly coordinated regulation of microRNA expression profiles. These findings highlight promising candidate loci and biomarkers for predicting the complicated course of atherosclerosis, which warrants further validation in larger independent cohorts.
SN - 2296-634X
ER -