Clinical Epigenetics最新文献

{"title":"HCV patients with residual fibrosis after DAA treatment re-establish their epigenetic signature after prolonged-release pirfenidone: MINERVA study.","authors":"Eira Cerda-Reyes, Ricardo de la Rosa-Bibiano, Ana Sandoval-Rodriguez, Rebeca Rosas-Campos, Aldo Torre, Stefanny Cornejo-Hernández, Rebeca Escutia-Gutiérrez, Ángel Vázquez-Esqueda, Jorge Gutierrez-Cuevas, Alejandro Gutiérrez-Átemis, Salvador Amezquita-Pérez, Jorge Luis Poo, Gildardo Agustin Garrido-Sánchez, Javier Bastida-Alquicira, Elsa Saldaña-Rivera, Lucila Maritza Lozano-Trenado, Juan Ramón-Aguilar, Jose Alejandro Madrigal, Juan Armendariz-Borunda","doi":"10.1186/s13148-025-01969-y","DOIUrl":"10.1186/s13148-025-01969-y","url":null,"abstract":"<p><strong>Background & aims: </strong>Patients with residual liver fibrosis after hepatitis C virus infection clearance represent an important challenge. The primary objective of this study was to evaluate epigenetic marks in DAA-responders HCV, Hispanic patients with remaining fibrosis who were treated with prolonged-release pirfenidone (PR-PFD).</p><p><strong>Methods: </strong>Forty-four DAA-responders HCV patients presenting remaining fibrosis received PR-PFD (1200 mg/day) for 12 months. Liver biopsies and serum samples were analyzed. Patients were classified as regressive fibrotic profile (RFP), stable fibrosis profile (SFP), or progressive fibrotic profile (PFP) based on liver stiffness (Fibroscan) (± 30% variation). A control cohort of 20 DAA-responders HCV patients received only standard of care treatment. Additionally, six non-fibrotic controls were included to compare epigenetic marks.</p><p><strong>Results: </strong>Thirty-eight patients completed the 12-month treatment; 28.94% showed a reduction in at least one fibrosis stage based on liver biopsies. Fibroscan revealed that 44.73% of patients in the PR-PFD group exhibited RFP. Bilirubin, alkaline phosphatase, AST, INR and APRI values significantly decreased in this group. Noteworthy, 85% of 20 control patients had SFP. Profibrogenic miRNAs displayed a significant increase in expression in advanced fibrosis versus controls without fibrosis. PR-PFD treatment restored the expression of miR-34a, miR-16, miR-192, miR-200a, and miR-122. PDGFA CpGs hypermethylation in both cell-free DNA and liver biopsies has been found in advanced fibrosis. Interestingly, four CpGs in PPARD were hypomethylated compared to controls. PR-PFD treatment resulted in hypermethylation of three TGFB1-CpGs.</p><p><strong>Conclusion: </strong>These findings indicate for the first time that PR-PFD might exert therapeutic effects in Hispanic patients with residual fibrosis by modulating the expression of miRNAs and methylation of specific CpG sites.</p><p><strong>Clinical trial number: </strong>NCT05542615. Registration Date 09/13/2022.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"157"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225337","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":"In-utero exposure to maternal diabetes and DNA methylation alterations in the Next Generation birth cohort.","authors":"Ola E Salama, Yash Rawal, Priscilla Irabor, Haziqa Kassim, Christy Pylypjuk, Elizabeth A C Sellers, Brandy A Wicklow, Meaghan J Jones","doi":"10.1186/s13148-025-01972-3","DOIUrl":"10.1186/s13148-025-01972-3","url":null,"abstract":"<p><strong>Introduction: </strong>The incidence of type 2 diabetes (T2D) in youth is increasing and in-utero exposure to maternal diabetes is a known risk factor, with higher risk associated with pregestational T2D exposure compared to gestational diabetes mellitus (GDM) exposure. We hypothesize this differential risk is reflected in DNA methylation (DNAm) changes induced by differential timing of in-utero exposure to maternal diabetes, and that exposure to diabetes throughout pregnancy (T2D) compared to exposure later in development (GDM), induces different DNAm signatures and different T2D risk to offspring. This study presents an epigenome-wide investigation of DNAm alterations associated with in-utero exposure to either maternal pregestational T2D or GDM, to determine if the timing of prenatal diabetes exposure differentially alters DNAm.</p><p><strong>Methods: </strong>We performed an epigenome-wide analysis on cord blood from 99 newborns exposed to pregestational T2D, 70 newborns exposed to GDM, and 41 unexposed to diabetes in-utero from the Next Generation birth cohort. Associations were tested using multiple linear regression models while adjusting for sex, maternal age, BMI, smoking status, gestational age, cord blood cell type proportions and batch effects.</p><p><strong>Results: </strong>We identified 27 differentially methylated sites associated with exposure to GDM, 27 sites associated with exposure to T2D, and 9 common sites associated with exposure to either GDM or T2D (adjusted p value < 0.05 and effect size estimate > 0.01). One site at CLDN15 and two unannotated sites were previously reported as associated with obesity. We also identified 87 differentially methylated regions (DMRs) associated with in-utero exposure to GDM and 69 DMRs associated with in-utero exposure to T2D. We identified 23 DMR sites that were previously associated with obesity, three with T2D and five with in-utero exposure to GDM. Furthermore, we identified six CpG sites in the PTPRN2 gene, a gene previously associated with DNAm differences in blood of youth with T2D from the same population.</p><p><strong>Conclusion: </strong>Our findings support that in-utero exposure to maternal diabetes is associated with DNAm alterations in offspring. Moreover, the timing of maternal diabetes in-utero exposure (GDM or T2D) produces overlapping but distinct DNAm patterns, suggesting that the window of exposure to maternal diabetes produces different molecular modifications and may reflect, at least in part, the difference in risk for youth-onset T2D in offspring. We also identified sites in this study that have been previously associated with T2D or obesity, which may serve as potential early-life biomarkers of exposure and/or risk, warranting further investigation in longitudinal studies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"165"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225285","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":"Cadmium and Chromium exposure associated with DNA hypermethylation of p16 tumor suppressor gene: a case-control study from endemic region of northern India.","authors":"Runjhun Mathur, Gaurav Saini, Sheo Prasad Shukla, Abhimanyu Kumar Jha","doi":"10.1186/s13148-025-01957-2","DOIUrl":"10.1186/s13148-025-01957-2","url":null,"abstract":"<p><p>This study investigates the environmental impact of urbanization on water quality in Greater Noida, a rapidly developing region in India. Thirty groundwater samples were collected from five villages during the pre-monsoon season using sterilized polypropylene bottles, and samples were acidified and digested with concentrated nitric acid prior to analysis. Chromium (Cr) and cadmium (Cd) concentrations in water were determined using Atomic Absorption Spectrophotometry (AAS), with mean pre-monsoon concentrations of 0.436 ± 0.237 ppb for Cr and 0.224 ± 0.091 ppb for Cd. A case-control study involving 25 cancer patients and 25 healthy individuals was conducted to explore the potential health effects of heavy metal exposure through drinking water. Blood samples were analyzed for Cd and Cr levels, and p16 gene promoter hypermethylation was assessed in whole blood leukocytes using methylation-specific PCR (MSP). The frequency of p16 hypermethylation was significantly higher in the exposed group (64%) compared to controls (8%) (p = 0.002). These findings demonstrate a strong association between heavy metal exposure and p16 hypermethylation, emphasizing the need for comprehensive monitoring, control measures, and remediation strategies to address environmental contamination and safeguard public health in swiftly urbanizing regions like Greater Noida.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"162"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225239","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":"Seminal plasma cfDNA fragmentomics landscape delineates male infertility subtypes.","authors":"Xiaoyu Wu, Fan Meng, Huiping Zhang, Zeqing Li, Kai Zhao","doi":"10.1186/s13148-025-01973-2","DOIUrl":"10.1186/s13148-025-01973-2","url":null,"abstract":"<p><strong>Background: </strong>While cell-free DNA (cfDNA) fragmentomics has transformed liquid biopsy applications in prenatal screening and oncology, its potential in male reproductive health remains unexplored.</p><p><strong>Methods: </strong>Through integrated whole-genome sequencing and jagged end sequencing (Jag-Seq) coupled with non-CG(CH) methylation analysis, we established the first fragmentomic atlas of seminal plasma (SP) cfDNA from 18 healthy donors, with 20 plasma cfDNA samples. This approach was then applied to 33 patients (14 with varicocele [VC] and 19 with nonobstructive azoospermia [NOA]) to characterize disease-specific fragmentomic features. ROC analysis was employed to study the potential diagnostic ability for these two diseases.</p><p><strong>Results: </strong>Size distribution profiling showed SP cfDNA enrichment in short fragments (< 150 bp) with bimodal distribution (151 bp main peak/110 bp subpeak), contrasting with plasma's sharp 166-bp peak pattern ( <math><mrow><mi>P</mi> <mo><</mo> <mn>0.001</mn></mrow> </math> ). Motif analysis identified SP-specific patterns: increased AAAA-end motif frequency and a strong A-base preference at positions - 2 to - 4. SP showed higher jagged end index based on Jag-Seq ( <math><mrow><mi>P</mi> <mo><</mo> <mn>0.0001</mn></mrow> </math> ). In disease states, VC exhibited 7 altered frequency motifs and longer jagged end length, while NOA demonstrated higher methylation level at CH sites. Integrating these fragmentomic features, ROC analysis achieved 83% accuracy in distinguishing VC and 87% accuracy in distinguishing NOA.</p><p><strong>Conclusions: </strong>The study indicates that distinct cfDNA profiles are present in certain male infertility conditions. These cfDNA metrics demonstrated disease-specific cfDNA dynamics present innovative opportunities for the development of noninvasive diagnostic tools in the field of reproductive medicine.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"163"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225040","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":"Maternal glucose concentrations and DNA methylation of genes related to the PPAR signaling pathway in human placenta: insights for maternal glucose concentrations' effects on neonatal anthropometrics.","authors":"Likang Li, Lei Zhang, Yafei Chen, Fen Yang, Xiuxia Song, Hong Liang, Wei Yuan, Honglei Ji, Min Luan, Maohua Miao","doi":"10.1186/s13148-025-01974-1","DOIUrl":"10.1186/s13148-025-01974-1","url":null,"abstract":"<p><strong>Background: </strong>Accumulating evidence indicates that elevated maternal glucose concentrations during pregnancy are associated with adverse birth outcomes, but the mechanistic underpinnings remain unclear. This study aimed to evaluate the associations between maternal glucose concentrations and DNA methylation levels in genes related to the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the human placenta and explore the potential mediating role of placental DNA methylation in the relationship between maternal glucose concentrations and neonatal anthropometric measures.</p><p><strong>Methods: </strong>Maternal glucose concentrations were obtained from medical records, and neonatal anthropometric parameters were measured in 335 mother-infant pairs. DNA methylation levels of 14 genes related to the PPAR signaling pathway were analyzed in placental samples. Multiple linear regression models and mediation analyses were used to examine the associations and potential mediation effects.</p><p><strong>Results: </strong>Higher maternal fasting plasma glucose (FPG) concentrations were generally associated with hypomethylation of genes related to the PPAR signaling pathway, with stronger effects in male neonates. Maternal 1-h plasma glucose concentrations after the glucose challenge test exhibited weaker but consistent patterns. Mediation analyses indicated that hypomethylation of ACAA1 mediated 29.00% (Indirect effect [IE]: β = 0.07; 95% confidence interval [CI] 0.02, 0.14) and 21.75% (IE: β = 0.07; 95% CI 0.00, 0.18) of the effects of FPG concentrations on increased neonatal abdominal and back skinfold thickness, respectively, while ACADM hypomethylation mediated 15.39% (IE: β = 0.03; 95% CI 0.00, 0.08) and 17.69% (IE: β = 0.06; 95% CI 0.00, 0.13) of these effects.</p><p><strong>Conclusions: </strong>Elevated Maternal glucose concentrations were associated with hypomethylation of genes related to the PPAR signaling pathway. Specifically, hypomethylation of ACAA1 and ACADM may partially mediate the impact of maternal glucose concentrations on increased neonatal anthropometric measures. These findings provide mechanistic insights into potential epigenetic pathways linking maternal glucose concentrations to neonatal anthropometric outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"159"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225022","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":"Highly variable genomic methylation in the Beckwith-Wiedemann syndrome associated with multi-locus imprinting disturbances.","authors":"Francesco Cecere, Laura Pignata, Emilia D'Angelo, Carlo Giaccari, Abu Saadat, Angela Sparago, Claudia Angelini, Bruno Hay Mele, Alessandro Mussa, Giovanni Battista Ferrero, Gioacchino Scarano, Giulia Gori, Emilio Di Maria, Corrado Romano, Luigi Tarani, Carmelo Piscopo, Iris Scala, Jair Antonio Tenorio, Pablo Lapunzina, Flavia Cerrato, Andrea Riccio","doi":"10.1186/s13148-025-01971-4","DOIUrl":"10.1186/s13148-025-01971-4","url":null,"abstract":"<p><strong>Background: </strong>The expression of imprinted genes, which depends on their gamete of origin, is regulated by DNA sequences characterized by differential methylation between the maternal and paternal alleles (also known as germline differentially methylated regions or gDMRs). The most common molecular defect associated with Beckwith-Wiedemann syndrome (BWS), a condition linked to overgrowth and tumours, is the loss of methylation of the KCNQ1OT1-TSS gDMR located on chromosome 11p15.5 (also known as IC2 LoM). Approximately one-third of BWS patients with IC2 LoM exhibit multi-locus imprinting disturbances (MLID). While maternal-effect variants in proteins of the oocyte subcortical maternal complex (SCMC) have been linked to MLID, the underlying mechanisms and health impact of this epigenetic disturbance remain unclear.</p><p><strong>Results: </strong>We used the Infinium EPIC methylation array to investigate whole-genome CpG methylation in 64 BWS patients with IC2 LoM and 37 control subjects. We distinguished two patient groups, one with a variable methylation level of 24 gDMRs and the other with single-locus IC2 LoM. We observed that the mothers of the former patient group carried more variants in maternal-effect genes than those of the latter group, and 50% of them, but none of the latter group had variants in the SCMC genes. Additionally, in the former group, the mothers were older at the time of pregnancy, and the patients showed higher variation in methylation levels of thousands of CpGs located in non-imprinted loci, including protochaderins and cancer-associated genes. We found no differences in clinical features or in the incidence of assisted reproductive technology between the two patient groups. However, multiple affected siblings and recurrent miscarriages were observed only among cases with biallelic maternal-effect SCMC gene variants.</p><p><strong>Conclusions: </strong>This study demonstrates that the BWS patients with MLID exhibit highly variable methylation changes that affect both imprinted and non-imprinted loci in a seemingly stochastic manner throughout the genome. These findings support the hypothesis that MLID results from the interaction of maternal-effect genes and environmental factors in aged oocytes, leading to disordered DNA methylation in the whole genome. Future research should investigate whether and how these epimutations impact the health of affected individuals, particularly in adulthood.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"160"},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225350","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":"Multiple functions of the lysine methyltransferase KMT5a in cancer: potential targets for innovative therapies.","authors":"Rosa Della Monica, Michela Buonaiuto, Mariella Cuomo, Davide Costabile, Claudio Schonauer, Giuseppe Catapano, Lorenzo Chiariotti, Roberta Visconti","doi":"10.1186/s13148-025-01980-3","DOIUrl":"10.1186/s13148-025-01980-3","url":null,"abstract":"<p><p>Lysine methyltransferase 5a (KMT5a) plays a key role in the pathogenesis of many human diseases. Here, we review the diverse impacts of KMT5a activity on human cancer development and progression. First, KMT5a is the only Mammalian enzyme that specifically induces monomethylation of histone 4 (H4) on lysine 20, thus regulating chromatin organization and, in turn, the transcription of several oncogenes and tumor suppressor genes. KMT5a, by inducing H4 methylation, also critically establishes the choice between different pathways of DNA double-strand break repair, with important consequences for genomic instability and cancer origin. Finally, KMT5a also methylates lysine residues on nonhistone proteins, and KMT5a-induced methylation of key oncogenic and tumor suppressor proteins, including TP53, strongly affects cancer cell functions. Overall, KMT5a is overexpressed in a high percentage and wide variety of human cancers and has protumorigenic activity, which makes it a target for innovative therapy.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"152"},"PeriodicalIF":4.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191339","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":"The OGG1 Ser326Cys polymorphism: molecular mechanisms of disease susceptibility and precision medicine applications.","authors":"XueJian Wang, Bo Li, JingYa Gao, Kun Wang, SuMin Yang","doi":"10.1186/s13148-025-01978-x","DOIUrl":"10.1186/s13148-025-01978-x","url":null,"abstract":"<p><p>DNA molecules are susceptible to reactive oxygen species (ROS) attack leading to oxidative damage, of which 8-oxoguanine (8-oxoG) is a core oxidative marker. OGG1 acts as a DNA repair enzyme and maintains genomic stability by specifically repairing 8-oxoG through the base excision repair (BER) pathway. The Ser326Cys polymorphism significantly reduces enzyme activity and potentially impacts phosphorylation-mediated subcellular localization dynamics and epigenetic regulatory networks, thereby potentially exacerbating genomic instability. In this review, we analyzed the association between the OGG1 Ser326Cys polymorphism and different diseases, such as risk, platinum-based chemotherapy sensitivity, and radiotherapy toxicity in cancer. In neurodegenerative disorders, the Cys326 type leads to the accumulation of 8-oxoG in neurons and accelerates CAG triplet repeat amplification. In metabolic disorders, its insufficient repair may trigger β-cell dysfunction, which increases the risk of type 2 diabetes mellitus. Finally, we integrated multiomics data and proposed a genotype-based precision intervention strategy to provide a theoretical basis for disease risk prediction, personalized therapy, and novel targeted drug development.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"153"},"PeriodicalIF":4.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191320","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":"ALYREF inhibits ferroptosis in vascular endothelial cells and improves atherosclerosis by epigenetic modification of CISD1.","authors":"Jinghai Hua, Ling Yu, Wenjun Xiong, Ru Ying, Qiong Duan, Jianbing Zhu, Xiaoping Peng, Minzi Qiu","doi":"10.1186/s13148-025-01955-4","DOIUrl":"10.1186/s13148-025-01955-4","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis (AS) is a disease marked by lipid metabolism dysfunction. Methylation of 5-methylcytosine (m⁵C) mRNA can regulate AS progression. We investigated the role and mechanism of m⁵C reader ALYREF in AS.</p><p><strong>Methods: </strong>ApoE^-/- mice AS models were constructed. Oil Red O staining evaluated the degree of aortic plaque. Serum LDL and TG levels were assessed. ELISA detected vascular inflammation and ATP production. Expressions of ALYREF, CISD1, and ferroptosis-related proteins were detected by RT-qPCR and Western blot. CCK-8, EdU, and flow cytometry were used to detect cell viability and apoptosis. RIP assay validated the direct binding of ALYREF to CISD1. Mitochondrial morphology was observed by transmission electron microscopy (TEM). Mitochondrial membrane potential was determined by JC-1. Mitochondrial ROS and cytoplasmic ROS were tested by immunofluorescence staining. Oxidative stress damage (MDA), antioxidant enzymes (SOD/GSH), and Fe²⁺ levels were detected by kits. Methylated RNA was immunoprecipitated with m⁵C-specific antibody (MeRIP).</p><p><strong>Results: </strong>ALYREF expression declined in AS mice and human primary coronary artery endothelial cells (HCAEC) induced by oxidized low-density lipoprotein (ox-LDL). Elevated ALYREF improved ox-LDL-induced HCAEC apoptosis, inflammation, and lipid metabolism. ALYREF elevation attenuated mitochondrial damage and ferroptosis in ox-LDL-exposed HCAEC. ALYREF facilitated the stability and expression of CISD1 mRNA through m⁵C methylation. Reversing CISD1 expression negated the protective effects of ALYREF overexpression against ox-LDL-induced HCAEC damage. ALYREF-mediated epigenetic modification of CISD1 alleviated AS progression by reducing lipid levels and inhibiting ferroptosis in vivo.</p><p><strong>Conclusion: </strong>By enhancing m⁵C modification, ALYREF enhances the stability and expression of CISD1 mRNA, which impedes lipid metabolism and endothelial cell ferroptosis in AS and alleviates AS-associated pathological changes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"151"},"PeriodicalIF":4.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136751","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 sequencing-derived methylation biomarker prediction for methylation-specific PCR in patients with head and neck squamous cell carcinoma.","authors":"Daria Meyer, Anne Hennig, Anna-Bawany Hums, Orlando Guntinas-Lichius, Martina Schmitz, Manja Marz","doi":"10.1186/s13148-025-01960-7","DOIUrl":"10.1186/s13148-025-01960-7","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation of CpG islands is altered in cancer cells. Hypermethylation of single CpG islands in the promoter regions of tumor-suppressor genes occurs already in the early stages of cancer. These methylation changes are cancer-type specific and therefore can serve as early cancer biomarker. Identifying good and reliable biomarkers is crucial for the development of diagnostic tests and their application in clinical practice and remains the most significant challenge to date.</p><p><strong>Results: </strong>Here, we present a generic workflow for the discovery and design of DNA methylation-specific PCR (MSP) biomarkers using nanopore sequencing. We show that nanopore sequencing of three control and three tumor tissue samples was sufficient to predict differentially methylated regions between head and neck squamous cell carcinoma (HNSCC) and healthy control tissue samples and to design functional MSP primers. When applied to a validation cohort of 48 HNSCC and 46 control samples, four out of six designed MSP singleplex assays achieved good sensitivity and specificity with an AUC above 0.8.</p><p><strong>Conclusion: </strong>Our resulting DNA methylation-based workflow demonstrates how long-read methylation data enable the design of adaptable, clinically relevant epigenetic assays, even with low coverage and small initial sample numbers.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"149"},"PeriodicalIF":4.4,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058478","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}