Clinical Epigenetics最新文献

{"title":"Metastasis-associated DNA methylation of the lncRNAs LINC01354 and LINC01510 in clear cell renal cell carcinoma.","authors":"Pouriya Faraj Tabrizi, Inga Mareike Schimansky, Inga Peters, Mohammed Rafea Kanaan, Jörg Hennenlotter, Andre Franke, Hossein Tezval, Markus Antonius Kuczyk, Jürgen Serth","doi":"10.1186/s13148-026-02252-4","DOIUrl":"10.1186/s13148-026-02252-4","url":null,"abstract":"<p><strong>Background: </strong>Long non-coding RNAs (lncRNAs) regulate multiple cellular processes and are involved in the development and progression of human cancers, including renal cell carcinoma (RCC).</p><p><strong>Methods: </strong>Genome-wide DNA methylation profiling using Illumina EPIC arrays was performed to identify differentially methylated regions (DMR) associated with metastatic RCC. Candidate loci within LINC01354 and LINC01510 were validated by pyrosequencing in 145 primary RCC tissues, 124 paired tumor-adjacent normal tissues (adNs), and 194 metastatic tissue samples obtained from 101 patients with metastatic RCC. In addition, data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma Collection (TCGA-KIRC) were analyzed in silico to assess the clinical relevance of DNA methylation (DNAm) and its association with gene expression.</p><p><strong>Results: </strong>Hypermethylation across all analyzed CpG sites at both loci was associated with high-stage (≥ T3; p = 0.001) and high-grade (≥ G3; p = 0.003) RCC and was markedly increased in metastatic tissues compared with localized primary tumors (p < 0.001). In addition, primary tumors from patients with distant metastases (M+) showed significantly higher methylation at PS_307-CG1 within LINC01510 than tumors from patients without distant metastases (M0; p = 0.031). Analyses of TCGA-KIRC data confirmed associations of increased methylation with adverse clinicopathological features and reduced gene expression, supporting a potential role for epigenetic silencing.</p><p><strong>Conclusion: </strong>Our data provide further insight into the epigenetic alterations associated with RCC progression by demonstrating tumor- and metastasis-associated hypermethylation at the LINC01354 and LINC01510 loci. The association of hypermethylation with advanced disease and metastatic tissues, together with the observed inverse relationship between methylation and expression, suggests that epigenetic inactivation of these lncRNAs may contribute to RCC progression. DNAm at these loci may therefore represent a potential biomarker of aggressive disease.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia.","authors":"Ugo Sorrentino, Nazanin Mirza-Schreiber, Martin Pavlov, Fatemeh Peymani, Petra Havrankova, Elisabetta Indelicato, Tereza Serranová, Lukas Kunc, Sandy Lösecke, Erik Tilch, Sebastian Eck, Holger Prokisch, Juliane Winkelmann, Sylvia Boesch, Robert Jech, Elisabeth Graf, Konrad Oexle, Michael Zech","doi":"10.1186/s13148-026-02243-5","DOIUrl":"10.1186/s13148-026-02243-5","url":null,"abstract":"<p><p>Diagnosis of KMT2B-related dystonia remains challenging due to the high prevalence of variants of uncertain significance and technological constraint of short-read pipelines. To overcome these limitations, we integrated nanopore-based long-read sequencing with a validated KMT2B-episignature classifier to perform simultaneous genetic and epigenetic profiling for three cases with prior uncertain KMT2B-related findings. Our workflow detected characteristic deviations in the KMT2B-episignature score in two cases with previously unresolved or missed KMT2B variants, while refuting an ambiguous indel call. Combining genomic-variant detection with DNA-methylation analysis eliminated the need for sequential testing and enhanced accurate diagnosis of KMT2B-related dystonia, offering a basis for streamlined epigenetics-guided diagnostics.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic clocks can differentiate between exogenous and endogenous skin ageing.","authors":"Christopher J Shore, Roy B Simons, Laura Ramos Del Caño, Ziyi Xiong, Luba Milena Pardo, Christina M W Eecen, Tamar Nijsten, Kerrin S Small, Athina Vidaki, Manfred Kayser, Jordana T Bell, Y Jeremy Shen, David A Gunn","doi":"10.1186/s13148-026-02230-w","DOIUrl":"10.1186/s13148-026-02230-w","url":null,"abstract":"<p><strong>Context: </strong>Whereas factors originating internally to the body, such as blood nutrients and hormones, influence endogenous skin ageing, exogenous skin ageing results from the penetration of harmful factors through the skin's outer stratum corneum layer.</p><p><strong>Aim: </strong>To test whether an exogenous skin ageing epigenetic clock is more strongly associated with aspects of sun-exposure than two endogenous epigenetic clocks.</p><p><strong>Methods: </strong>Exogenous and endogenous skin clocks were trained in more than 400 skin samples. These two clocks and the Horvath 'Skin and Blood' epigenetic clock were tested for association with chronological age and, whilst controlling for chronological age (age acceleration), sun-exposure parameters and skin gene expression.</p><p><strong>Results: </strong>Exogenous Skin clock ages were significantly (p<0.001) older in both epidermal (n=24) and cultured fibroblast (n=8) sun-exposed arm samples than in donor matched sun-protected samples. Exogenous Skin clock age acceleration was significantly correlated (Rho = 0.18, p = 0.004) with sun-seeking behaviour and mRNA levels (202 genes had q < 0.05) in whole skin abdomen samples (n=364); the latter was consistent with sun-exposed versus sun-protected older arm mRNA differences (n=12 donors). In 44 facial skin swabs, exogenous age acceleration was also significantly correlated with facial photodamage grading (rho = 0.33, p = 0.028). Although the Endogenous and Skin and Blood clocks were more strongly correlated with chronological age, their age acceleration estimates were not significantly associated with sun-exposure parameters or mRNA levels in skin.</p><p><strong>Conclusion: </strong>Skin epigenetic clocks can differentiate exogenous from endogenous skin ageing facilitating further study of the mechanisms underlying these two skin ageing phenomena.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BLEND-M: cellular deconvolution with personalized DNA methylation references.","authors":"Penghui Huang, David G Peters, Chris McKennan","doi":"10.1186/s13148-026-02223-9","DOIUrl":"https://doi.org/10.1186/s13148-026-02223-9","url":null,"abstract":"<p><strong>Background: </strong>Cellular deconvolution estimates cell type fractions in tissue samples, providing an in-silico alternative to costly and labor-intensive cell sorting techniques. Accurate fraction estimates are essential for DNA methylation (DNAm) analyses, as they enable adjustment for confounding, support risk prediction models, and facilitate cell type-specific (CTS) differential methylation analyses. A key determinant of deconvolution accuracy is the choice of CTS reference profiles, which represent expected DNAm levels in each cell type. Although it is widely recognized that CTS DNAm levels vary substantially across individuals, existing methods assume a shared reference across the population, leading to biased fraction estimates.</p><p><strong>Results: </strong>We introduce BLEND-M, a novel method for deconvolving bulk DNAm data that learns personalized CTS reference profiles for each bulk sample. In addition to accounting for inter-individual variability in CTS DNAm, BLEND-M explicitly models heteroscedasticity across marker CpGs-the fact that DNAm measurements at some CpGs are noisier than others-thereby improving robustness to noisy markers. We establish theoretical guarantees for the accuracy of BLEND-M and demonstrate its improved performance relative to existing methods through extensive benchmarking on realistic simulated and real datasets. We further illustrate its practical utility by applying BLEND-M to develop a risk prediction model for childhood atopic asthma.</p><p><strong>Conclusion: </strong>BLEND-M improves the accuracy and robustness of DNAm deconvolution by accounting for inter-individual variability in CTS DNAm. These advances enhance downstream analyses, including risk prediction, confounding adjustment, and CTS differential methylation studies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-omics Mendelian randomization framework identifies PM2.5-annotated candidate regulatory genes and methylation-linked pathways in diabetic nephropathy.","authors":"Hao Zhang, Peijun He, Feihong Ren, Haojun Zhang, Fang Ma, Huimin Mao, Yuyang Wang, Tingting Zhao, Ping Li, Xin Yang, Tongtong Liu, Qi Jin, Yongli Zhan, Liping Yang","doi":"10.1186/s13148-026-02215-9","DOIUrl":"10.1186/s13148-026-02215-9","url":null,"abstract":"<p><strong>Background: </strong>Fine particulate matter (PM2.5) is an established environmental risk factor for chronic kidney disease, yet the molecular pathways linking PM2.5 exposure to diabetic nephropathy (DN) progression remain to be elucidated. This study employs a multi-omics causal inference framework to identify and characterize candidate genetic and epigenetic mediators that may underlie this association.</p><p><strong>Methods: </strong>Utilizing a curated set of PM2.5-annotated genes, we performed summary-data-based Mendelian randomization (SMR) analyses, integrating expression, protein, and methylation quantitative trait loci (eQTLs, pQTLs, mQTLs) with DN genome-wide association study (GWAS) summary statistics. Bayesian colocalization was used to distinguish shared from distinct causal variants. The expression of prioritized genes was validated in an independent DN transcriptomic dataset (GSE96804) and through in vitro PM2.5 exposure experiments. A predictive nomogram for DN risk was subsequently developed and evaluated.</p><p><strong>Results: </strong>Transcript-level SMR identified ten PM2.5-associated genes (e.g., TNF, NOS2, DUSP1) with genetically predicted causal effects on DN susceptibility. Bayesian colocalization revealed strong evidence for a shared causal variant only at EIF2AK3 (PP.H4 = 0.90). Methylation analysis revealed 48 CpG sites significantly associated with DN risk, mapping to 28 genes, with TNF methylation showing the strongest effect. Multi-omics integration and protein-protein interaction analysis highlighted TNF as a central hub within an enriched inflammatory network. Furthermore, mQTL-eQTL SMR showed that hypermethylation at cg11484872 suppressed TNF, whereas methylation at cg14968860 and cg18091275 upregulated DUSP1 and NOS2, respectively, establishing bidirectional epigenetic regulation of these genes. In DN kidney tissue, TNF and NOS2 were upregulated while DUSP1 was downregulated, and these changes were recapitulated in cellular models following PM2.5 exposure. A nomogram based on NOS2 and TNF yielded an AUC of 0.766 in the training set and 0.726 in an independent external cohort (GSE142153).</p><p><strong>Conclusion: </strong>Our integrative analysis identifies a PM2.5-responsive epigenetic-gene regulatory network involving TNF, NOS2, and DUSP1 that may represent candidate mediators of PM2.5-related DN progression. These findings nominate molecular candidates for environmental kidney injury and highlight potential biomarkers for risk stratification.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13741707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroepigenetic programming by the maternal environment. Part B: independent contribution of methylation and hydroxymethylation in the offspring's olfactory bulb following preconceptional weight loss in mice.","authors":"Karine Badonnel, Aurélie Chaulot-Talmon, Valentin Costes, Anne Frambourg, Gabriel Costa-Monteiro-Moreira, Mélanie Jouin, Lorraine Bourgeois-Brunel, Anne Gabory, Hélène Kiefer, Hélène Jammes, Christine Baly","doi":"10.1186/s13148-026-02175-0","DOIUrl":"10.1186/s13148-026-02175-0","url":null,"abstract":"<p><strong>Background: </strong>Recent studies indicate that inadequate maternal diet can influence offspring physiology, metabolism and cognitive health, but the impact of the preconception period remains largely unexplored. We previously showed that maternal weight loss prior to conception affects metabolic outcomes and olfactory-driven behaviors in mouse offspring. To explore whether these intergenerational effects are linked to epigenetic mechanisms in the olfactory bulb (OB), we investigated changes in DNA methylation, specifically 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), the latter being relatively abundant in the brain but still poorly characterized.</p><p><strong>Results: </strong>We profiled DNA methylation and hydroxymethylation using Reduced Representation Bisulfite Sequencing (RRBS) and oxidative RRBS (oxRRBS) on OBs from offspring born to control or weight loss mothers, to enable a distinct quantification of 5mC and 5hmC levels at the same CpG sites. While 5mC was globally more abundant in the OB, a subset of CpGs showed high 5hmC levels that varied with maternal condition. Differential analysis identified more differential hydroxymethylated CpG (DhMCs, n = 2631) than differential methylated positions (DMC, n = 1834), indicating a stronger impact of maternal WL on hydroxymethylation. Both DMCs and DhMCs were enriched in genes involved in synaptic function, neuronal signaling, and energy metabolism. However, uniquely modified CpGs, i.e. those detected as modified in only one assay (RRBS or oxRRBS), revealed distinct functional profiles: uniquely differentially hydroxymethylated CpGs (uniqDhMCs) were enriched in genes related to neuronal activity and plasticity, while uniquely differentially methylated CpGs (uniqDMCs) were associated with chromatin remodeling and transcriptional regulation. These findings suggest that, although 5mC and 5hmC can impact similar pathways, they contribute differently to gene regulation in response to early-life nutritional environments.</p><p><strong>Conclusion: </strong>Our study highlights the feasibility of integrating 5mC and 5hmC analyses and uncovers their distinct genomic distributions. The maternal preconceptional weight loss induces lasting and specific epigenetic changes in the OB, notably through 5hmC-specific targeting on genes involved in neuronal activity. By distinguishing between shared and unique DMCs and DhMCs, we reveal complementary and functionally distinct contributions of 5mC and 5hmC to brain plasticity. These findings underscore the importance of integrating both epigenetic marks to fully understand how early-life environmental cues shape neural function and behavior.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13741425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promoter CpG island hypomethylation and overexpression of molecules homologous to the muscle autoantigens acetylcholine receptor and ryanodine receptor in thymoma epithelial cells associated with myasthenia gravis.","authors":"Yu Hong, Hai-Feng Li, Yanjun Guo, Lei Liu, Geir Olve Skeie, Jiawei Wang, Nils Erik Gilhus","doi":"10.1186/s13148-026-02213-x","DOIUrl":"10.1186/s13148-026-02213-x","url":null,"abstract":"<p><strong>Background: </strong>Thymoma-associated myasthenia gravis (TAMG) represents the paraneoplastic subtype of MG and is characterized by autoantibodies against skeletal muscle proteins, such as acetylcholine receptor (AChR), titin, and ryanodine receptor (RyR). Thymic epithelial cells of TAMG patients overexpress neuronal and neuromuscular genes that code for MG autoantigen epitopes. This may contribute to the autoimmune breakdown in TAMG patients. This study explored whether such aberrant expression of autoimmune epitopes is regulated by their promoter CpG methylation profiles.</p><p><strong>Methods: </strong>The thymoma bulk RNA sequencing, single cell RNA sequencing, and DNA methylation data were collected from 40 TAMG and 96 non-MG thymoma patients using three independent cohorts. A novel algorithm using a multiple linear regression model was developed to examine the gene promoter CpG island methylation status in TAMG and non-thymoma MG patients. The correlation between promoter CpG island and RNA expression in the TAMG thymoma was explored.</p><p><strong>Results: </strong>In both TAMG and non-MG thymoma, the global promoter CpG islands were hypomethylated and were negatively correlated with RNA expression. The CpG islands at promoters of muscle-like epitope genes, NEFM and RYR3, were significantly hypomethylated in TAMG thymoma and negatively correlated with mRNA expression in both a primary and a verification cohort. For MG antigen genes CHRNA1, TTN and RyR1, the CHRNA1 promoter CpG site methylation correlated negatively with CHRNA1 RNA expression. However, there was no difference in promoter methylation status between TAMG and non-MG thymomas. For the AIRE gene, the promoter CPG islands were significantly hypermethylated and negatively correlated with mRNA expression. Both bulk and single cell RNA sequencing showed that key genes involved in the DNA CpG methylation pathways, including DNMT1, UHRF1 and HDAC1, had a reduced expression in thymic epithelial cells of TAMG thymoma.</p><p><strong>Conclusions: </strong>Our results indicate that the aberrant overexpression of muscle-like epitopes in TAMG might be driven by CpG island hypomethylation. This represents a novel mechanism for intrathymic autoantigen regulation, relevant for the early pathogenesis of TAMG and thymoma-associated autoimmune disorders. Our findings should be verified in larger cohorts and with functional and histological validation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress and trends on epigenetics and endometriosis: a bibliometric analysis.","authors":"Xiaohua Li, Yiyun Bai, Sang Luo, Yiran Jin, Junxian Yang, Xiaxia An, Dan Liu","doi":"10.1186/s13148-026-02220-y","DOIUrl":"10.1186/s13148-026-02220-y","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis, a common gynecological disorder characterized by ectopic endometrial tissue, has complex epigenetic mechanisms. This study provides a comprehensive bibliometric analysis of research trends in endometriosis epigenetics.</p><p><strong>Methods: </strong>Articles on endometriosis epigenetics published from 2005 to 2026 were analyzed using the R package \"bibliometrix,\" VOSviewer, and CiteSpace to visualize research hotspots, key contributors, and emerging topics.</p><p><strong>Results: </strong>A total of 1175 articles were included, with the China leading (442 publications). Fudan University is the top institutions (76 articles, 6.4%), and Professor Taylor Hugh S. was the most prolific author (33 articles, 2.8%). Research hotspots included DNA methylation (notably HOXA10, SF-1, PR-B, ERβ, and GATA factors), histone modifications, and non-coding RNA regulation. Recent trends focus on novel epigenetic biomarkers and targeted therapies.</p><p><strong>Conclusions: </strong>This analysis highlights DNA methylation and non-coding RNAs as central in endometriosis epigenetics. Continued research should prioritize discovering biomarkers and translations into clinical practice.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Life's Simple 7 score and epigenetic age acceleration: associations and effect modification by race and ethnicity.","authors":"Nicholas Pryor, Darya Dokshina, Hanyang Shen, Nicole Gladish, Jennifer A Smith, David Rehkopf, Belinda L Needham","doi":"10.1186/s13148-026-02218-6","DOIUrl":"10.1186/s13148-026-02218-6","url":null,"abstract":"<p><strong>Background: </strong>Accelerated epigenetic aging is hypothesized to contribute to racial and ethnic disparities in cardiovascular outcomes. However, most measures of epigenetic age were developed in predominantly or exclusively White samples. To establish the utility of these measures for health disparities research, it is important to determine whether associations with health differ across racial and ethnic groups.</p><p><strong>Results: </strong>Using data from the National Health and Nutrition Examination Survey 1999-2002, we examined associations of the American Heart Association's Life's Simple 7 (LS7) cardiovascular health score with 13 standardized measures of epigenetic age among a nationally representative sample of non-Hispanic Black, non-Hispanic White, Mexican American, other Hispanic, and another race or ethnicity adults aged 50 to 84 (n = 2,401). In covariate adjusted models, a higher score on the LS7 was associated with lower epigenetic age acceleration on the Hannum (β = -0.032, 95% CI: -0.061, -0.004), PhenoAge (β = -0.052, 95% CI: -0.077, -0.026), GrimAge (β = -0.142, 95% CI: -0.171, -0.114), GrimAge2 (β = -0.158, 95% CI: -0.186, -0.130), DunedinPoAm (β = -0.142, 95% CI: -0.177, -0.108), and Telomere (β = 0.032, 95% CI: 0.010, 0.055) measures. Associations of LS7 with the Horvath, Weidner, Vidal-Bralo, Lin, SkinBlood, Zhang, and Yang measures were not statistically significant. With one exception for the Horvath measure, interactions between LS7 and race and ethnicity were non-significant.</p><p><strong>Conclusions: </strong>Better cardiovascular health was associated with lower epigenetic age acceleration, with insufficient evidence of differences by race and ethnicity. Associations were most consistent and robust for measures of epigenetic age trained on physiological age, suggesting that these measures may be useful for research on racial and ethnic disparities in cardiovascular outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13721615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149295177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation of silencer-annotated regions at the MGMT locus in the context of promoter and enhancer methylation in glioblastoma and melanoma brain metastases.","authors":"Katharina Pühringer, Fabian Firlinger, Benno Fehringer, Serge Weis, Sabine Spiegl-Kreinecker, Margit Cichna-Markl","doi":"10.1186/s13148-026-02204-y","DOIUrl":"10.1186/s13148-026-02204-y","url":null,"abstract":"<p><strong>Background: </strong>MGMT promoter methylation is a well-established biomarker in glioblastoma, its relevance in melanoma brain metastases remains controversial. Recent studies indicate that methylation of MGMT enhancers contributes to MGMT regulation, whereas the role of silencer methylation has not yet been investigated.</p><p><strong>Methods: </strong>DNA methylation of 52 CpG sites was analyzed in regions annotated as potential silencers located in the promoter, intronic, and upstream regions of MGMT. These regions were selected based on genomic annotations and their genomic proximity to MGMT, encompassing sites to approximately 1.5 Mb upstream, without experimental validation of direct regulatory activity. Analyses were performed in glioblastoma and melanoma brain metastases using in-house developed assays based on bisulfite conversion, PCR amplification of target regions, and pyrosequencing. By integrating previously published promoter and enhancer methylation data, a DNA methylation landscape of MGMT regulatory elements was established. Associations between CpG methylation and MGMT protein expression, overall survival, patient age, and sex were evaluated.</p><p><strong>Results: </strong>The degree of methylation strongly depended on the genomic location of the respective regulatory element. Both shared and tumor-type-specific methylation patterns were observed in glioblastoma and melanoma brain metastases. Promoter-associated CpGs and selected intronic silencer-annotated regions showed associations with MGMT protein expression. In glioblastoma, several promoter-associated CpGs were associated with overall survival, whereas sex-specific and age-related effects were absent.</p><p><strong>Conclusions: </strong>DNA methylation of MGMT regulatory elements is highly CpG-specific. CpG-resolved analyses reveal a complex epigenetic landscape across the MGMT locus and highlight substantial regional heterogeneity. These findings suggest that extending methylation analyses beyond the classical promoter region provides additional insights into MGMT-associated epigenetic variation and its potentical clinical associations.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13721255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149295229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}