Epigenetics最新文献

{"title":"Evaluating ancestry adjustment in multi-ancestry epigenome-wide analysis.","authors":"Yueming Liu, Alan Kuang, Marie-France Hivert, William L Lowe, Jami L Josefson, Denise M Scholtens","doi":"10.1080/15592294.2026.2646063","DOIUrl":"10.1080/15592294.2026.2646063","url":null,"abstract":"<p><p>Proper adjustment for population substructure is essential in epigenome-wide association studies (EWAS), particularly in cohorts with diverse ancestries. EPISTRUCTURE offers a genotype-free approach to ancestry inference, originally developed using a European reference population from the Cooperative Health Research in the Region of Augsburg (KORA) study. However, its effectiveness in genetically diverse, multi-ancestry cohorts remains insufficiently evaluated. For EWAS using cord-blood samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, we systematically assessed the ancestry adjustment performance of EPISTRUCTURE principal components (PCs) derived from the widely used KORA-based reference set versus new reference sets generated from genotyping data of the multi-ancestry HAPO cohort. HAPO-based reference sets were defined by varying SNP - CpG <math><mrow><msup><mi>R</mi><mn>2</mn></msup></mrow></math> thresholds (e.g. RS30: <math><mrow><msup><mi>R</mi><mn>2</mn></msup></mrow><mo>></mo><mn>0.3</mn></math>) to identify ancestry-informative CpGs. We applied these reference sets for population substructure adjustment in EWAS of three newborn adiposity traits, birthweight, cord C-peptide, and sum of skinfolds, to evaluate their impact on association detection and biological interpretation. Compared to the KORA reference, the HAPO RS30 reference consistently produced lower genomic inflation and identified more biologically relevant associations for birthweight and cord blood C-peptide in EWAS of HAPO cord blood samples (<i>n</i> = 3,116). Pathway enrichment analyses revealed strong immune and metabolic signals, including pathways uniquely captured by EWAS when using the HAPO-derived reference for ancestry adjustment. Trait enrichment using the EWAS Catalog further confirmed associations with fetal growth, maternal metabolic traits, and glucose regulation. Our findings demonstrate that reference sets derived from multi-ancestry cohorts like HAPO better capture underlying population substructure and improve ancestry adjustment in diverse EWAS settings.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2646063"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M6A-dependent regulation of microRNAs from CKD stage 5 patients: insights from epigenetic modification analysis.","authors":"Zhiqian Yang, Fanna Liu, Mingjun Ye, Qiang Yan, Zhipeng Zeng, Jingsheng Ma, Haitao Li, Hualin Ma, Xinzhou Zhang, Xiaofeng Zhu, Yong Dai, Donge Tang","doi":"10.1080/15592294.2026.2653962","DOIUrl":"10.1080/15592294.2026.2653962","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) stage 5 is frequently accompanied by systemic inflammation, and peripheral blood mononuclear cells (PBMCs) play an important role. To define the epitranscriptomic features of PBMC small RNAs in CKD stage 5, we profiled N6-methyladenosine (m6A) using small RNA modification microarrays. A total of 158 miRNAs, 149 pre-miRNAs, and 197 tsRNAs showed differential m6A modification. Enrichment analysis implicated PI3K-Akt, p53 signalling, and leukocyte transendothelial migration. Integrating target prediction with GEO transcriptomic datasets identified IRF1 and RUNX2 as key targets. MeRIP confirmed reduced m6A in miR-205-3p and miR-93-5p, accompanied by upregulation of RUNX2 and downregulation of IRF1 by qPCR. These results define an altered m6A-modification profile of PBMC small RNAs in CKD stage 5 and highlight miRNA-target gene axes with potential biomarker utility.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2653962"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSMA1, PSMA5, and PSMB2 serve as prognostic biomarkers and are correlated with tumor-infiltrating leukocytes in HCC.","authors":"Baitul Islam, Weiye Xu, Zaid Ur Rehman, Ru Zeng, Thekra Khushafa, Haiyang Yu, Jufang Huang","doi":"10.1080/15592294.2026.2726624","DOIUrl":"10.1080/15592294.2026.2726624","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death. Proteasome (PSM) is the main intracellular proteolytic system in higher eukaryotic cells. It has been reported to be involved in the tumor's onset, metabolism, and survival, and it has been recognized as a therapeutic target for many human cancers. The 20S proteasome subunits, specifically proteasome 20S subunit alpha 1 (PSMA1), proteasome 20S subunit alpha 5 (PSMA5), and proteasome 20S subunit beta 2 (PSMB2), are overexpressed in various malignancies, including HCC. Nevertheless, the exact role of these genes in HCC prognosis remains only partially understood. Moreover, a reliable predictive biomarker for HCC is essential for supporting the implementation of personalized therapies. Therefore, this study employed a comprehensive bioinformatics approach, integrating data from cBioPortal, Human Protein Atlas (HPA), Oncomine, STRING Viruses, Kaplan-Meier plotter, and other established high-throughput databases and tools. The current study thoroughly examined the expression levels, methylation, and genomic alterations of PSM and their correlation with tumor-infiltrating leukocytes. PSMA1, PSMA5, and PSMB2 are overexpressed in various cancers, including HCC, and their expression levels are associated with tumor grade and stage. The abundance of these genes is linked to diminished DNA methylation levels and genome alterations. Moreover, there was a significant association between the expression levels of these genes and poor prognosis and immune cell infiltration. In conclusion, this study proposes PSMA1, PSMA5, and PSMB2 as biomarkers for HCC.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2726624"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-parametric differential methylation analysis characterizes histotype-specific promoter regions in epithelial ovarian cancer.","authors":"Hugo Swenson, Ella Ittner, Lucas Werner, Elisabeth Werner Rönnerman, Szilárd Nemes, Toshima Z Parris, Khalil Helou","doi":"10.1080/15592294.2026.2720990","DOIUrl":"10.1080/15592294.2026.2720990","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) is a heterogenous disease with frequent late-stage diagnosis and high mortality rates, for which no reliable screening tests exist. In recent years, epigenetic biomarkers in the form of DNA methylation in CpG-rich regions have gained increased attention in the scientific community due to their robust nature and accessibility, allowing for diagnosis without the need for invasive surgery. In this study, we investigated the aberrant methylation of promoter regions in early stage EOC through non-parametric methods, with the purpose of characterizing candidate epigenetic biomarkers. The approach was used on a cohort of early stage EOC samples, and results were compared to existing programs for differential methylation. Significant regions were then used to construct a CpG panel for stratifying EOC histotypes through predictive classification in external data. Identified promoter regions were highly reproducible across cohorts, and the constructed CpG model stratified histotypes in external cohorts through predictive classification. Comparisons against other DMP and DMR callers showed a degree of homogeneity between results but also revealed promoter regions that were overlooked despite clear signs of aberrant methylation. Finally, EOC histotypes were found to differ in their methylation distribution types, and results indicate that methods sensitive to non-normally distributed data may be poorly suited to compare groups with different distribution types. The non-parametric approach identified aberrantly methylated promoter regions that were highly reproducible across cohorts. Results from predictive classification indicate that these regions may be useful for the purpose of EOC histotype stratification.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2720990"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pgRNA-m⁶A levels associate with HBV replication and liver function.","authors":"Chaoqi Yang, Shanshan Qin, Rui-Huan Gao, Anling Li, Shihui Song, Yidan Zhou, Song-Mei Liu","doi":"10.1080/15592294.2026.2726628","DOIUrl":"10.1080/15592294.2026.2726628","url":null,"abstract":"<p><p>m⁶A modification has been shown to play a role in regulating HBV RNA expression. However, it remains unclear whether the m⁶A levels of HBV pregenomic RNA (pgRNA) are related to HBV replication and liver function. Serum HBV pgRNA-m⁶A levels were determined by T3 DNA ligase assay. HBV DNA copy numbers and gene expression were detected by TaqMan assay and RT-qPCR, respectively. Liver function was evaluated using clinical laboratory indicators. The TET-off stable HBV-producing cell line HepAD38 and targeted pgRNA demethylation by SunTag system (TRADES) were used for the site-specific m⁶A editing. Flow cytometry was used to measure the cytokine levels in the supernatant of cell culture. Serum HBV pgRNA-m⁶A levels were positively correlated with HBV DNA copy number, pgRNA expression and liver function indicators (all <i>p</i> < 0.05). Both pgRNA-m⁶A levels and pgRNA expression were significantly increased in patients with high virus load (HBV DNA > 1.0 × 10⁷ IU/mL). Site-specific demethylation of pgRNA1907-m⁶A significantly reduced HBV DNA, hepatitis B e antigen (HBeAg) and HBV pgRNA, while induced levels of interferon alfa 2 (IFN-α2) and apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A). pgRNA-m⁶A modification of HBV associates with viral replication and liver function indicators. Site-specific m⁶A demethylation of pgRNA provides novel insight into anti-HBV treatment.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2726628"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dnmt1 associated <i>Gja1</i> promoter methylation changes are implicated in Cx43 remodeling during acute myocardial ischemia/reperfusion injury.","authors":"Yang Liu, Zijun Wang, Youxiao Zhao, Yanyan Ma, Jing Yi, Yingnan Song, Yanqiu Liu, Li An, Zhijun Pan, Hong Gao, Ying Cao","doi":"10.1080/15592294.2026.2694817","DOIUrl":"10.1080/15592294.2026.2694817","url":null,"abstract":"<p><p>DNA methylation has traditionally been regarded as a stable epigenetic modification. However, emerging evidence indicates that oxidative and genotoxic stress can induce locus-specific methylation changes that modulate transcriptional responses. The contribution of such dynamic regulation to cardiac gene expression during myocardial ischemia/reperfusion injury (MIRI) remains incompletely understood. This study investigated whether altered methylation changes within the <i>Gja1</i> promoter region are associated with connexin43 (Cx43) remodeling during MIRI. Male C57BL/6 mice were underwent global hypothermic I/R using a Langendorff-perfused heart model, with or without pretreatment using the DNA methyltransferase inhibitor 5-azacytidine (5-Aza, 3 μg/g body weight, i.p.). <i>Gja1</i> promoter methylation was analyzed by BSP and MSP, while Dnmt1 enrichment was assessed by chromatin immunoprecipitation. Cx43 expression and localization were examined by qRT-PCR, Western blotting, and immunofluorescence, together with electrophysiological and histological analyses. MIRI was associated with Dnmt1 upregulation and nuclear enrichment, accompanied by altered methylation signals at selected CpG sites within the examined <i>Gja1</i> promoter region and transcriptional repression. These changes coincided with reduced Cx43 expression, altered subcellular localization, impaired electrical conduction and increased arrhythmia susceptibility. Pretreatment with 5-Aza partially attenuated <i>Gja1</i> promoter methylation signals and preserved Cx43 expression and localization during subsequent MIRI. These findings support an association between Dnmt1 enrichment, altered<i>Gja1</i>promoter CpG methylation, and Cx43 remodeling under reperfusion stress, suggesting that methylation-related epigenetic regulation may participate in Gja1 transcriptional responses during MIRI. Further temporal and gene-specific validation will be required to establish the kinetics and causal specificity of this pathway.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2694817"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13336278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global analyses of genomic and epigenomic influences on gene expression reveal <i>Serpina3n</i> as a major regulator of cardiac gene expression in response to catecholamine challenge during heart failure.","authors":"Caitlin Lahue, Sriram Ravindran, Aryan Dalal, Rozeta Avetisyan, Christoph D Rau","doi":"10.1080/15592294.2026.2643094","DOIUrl":"10.1080/15592294.2026.2643094","url":null,"abstract":"<p><p>Heart failure arises from maladaptive remodelling driven by genetic and epigenetic networks. Using a systems genetics framework, we mapped how DNA variants and CpG methylation shape cardiac transcriptomes during beta adrenergic stress in the Hybrid Mouse Diversity Panel, a cohort of over 100 fully inbred mouse strains. Expression QTLs (eQTLs), methylation QTLs (mQTLs) and methylation-driven eQTLs (emQTLs) were generated from over 13k expressed genes and 200k hypervariable CpGs in left ventricles. We discovered hundreds of regulatory 'hotspots' that control large portions of the genome, including several that regulate over 10% of the transcriptome and/or methylome. Approximately 16% of these hotspots overlapped with prior GWAS or EWAS signals. We focus on a hotspot on chromosome 12 and identify the serpine peptidase inhibitor <i>Serpina3n</i>, as the most likely driver gene in this hotspot. Experimental knockdown of <i>Serpina3n</i> in neonatal rat ventricular cardiomyocytes blunted hypertrophy induced by a variety of hypertrophic signals, while altering predicted target expression and modulating the activity of <i>Nppa</i> and <i>Nppb</i>. Together, these findings position <i>Serpina3n</i> as a major regulator of stress-responsive cardiac gene programs, highlighting how integration of genetic and epigenetic signals can pinpoint key drivers of heart failure.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2643094"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A breast tissue-specific epigenetic clock provides accurate chronological age predictions and reveals de-correlation of age and DNA methylation in tumor-adjacent and tumor samples.","authors":"Leonardo D Garma, Sonia Pernas, Bartomeu Fullana, Andrea Vethencourt, David Vicente Baz, Teresa García Manrique, Rosario García Campelo, Cristina Reboredo, Josefa Terrasa, Antonia Perello, Ramón Colomer, Desirée Jiménez, Ruth Vera García, Susana de la Cruz Sánchez, Begoña Bermejo, Marta Tapia, Santiago González Santiago, Miguel Quintela-Fandino","doi":"10.1080/15592294.2026.2714582","DOIUrl":"10.1080/15592294.2026.2714582","url":null,"abstract":"<p><p>Epigenetic clocks have been widely used to estimate biological age across various tissues, but their accuracy in breast tissue remains suboptimal. Classical models such as Horvath's and Hannum's clocks perform poorly in predicting chronological age in breast tissue, underscoring the need for a tissue-specific approach. In this study, we introduce a Breast Tissue-specific Epigenetic Clock (BTEC), developed using DNA methylation data from 553 healthy breast tissue samples across seven different studies. BTEC significantly outperformed existing clocks, demonstrating superior correlation with chronological age (<i>r</i> = 0.91) and lower prediction errors (MAE = 3.0 y) without requiring dataset-specific regressions adjustments. Notably, BTEC showed consistent performance across ancestry groups, in contrast to existing clocks which exhibited variable ancestry-related biases. We also found that residual-based epigenetic age acceleration, commonly used to correct for prediction bias, is highly dependent on the choice of reference dataset and does not provide a generalizable correction. BTEC's chronological age predictions for tumor-adjacent samples showed distortions, with an average deviation of -2.3 y, which was even more pronounced in tumor samples, where the average difference between predicted and chronological age was -14 to -15 y. When analyzed by molecular subtype, the distortion was greater in the more aggressive HER2+ and TNBC tumors compared to HR+ tumors. Overall, our findings indicate that breast tumors do not generally exhibit accelerated epigenetic aging. The probes used by BTEC were associated with known oncogenes such as JAK1, TP73, PDGFRA, CCND1 and STAT5B, as well as genes involved in cancer-related pathways, including Wnt, Hedgehog and ErbB signaling. Importantly, extreme deviations in epigenetic age, as measured by BTEC-derived epigenetic age acceleration (EAA), were associated with patient survival in HR+ breast cancer patients in an exploratory analysis, highlighting the prognostic value of tissue-specific epigenetic aging measures. These findings demonstrate that BTECs not only improve age prediction in breast tissue but also capture biologically meaningful alterations in tumor epigenetic aging with potential clinical implications.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2714582"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of prenatal exposure to opioids, cannabis, and polysubstance use with cord blood DNA methylation patterns in a multiancestry cohort.","authors":"Henri Garrison-Desany, Ellen Howerton, Xiumei Hong, Brion Maher, Colleen Pearson, Barry Zuckerman, Guoying Wang, M Daniele Fallin, Terri Beaty, Liming Liang, Xiaobin Wang, Christine Ladd-Acosta","doi":"10.1080/15592294.2026.2670885","DOIUrl":"10.1080/15592294.2026.2670885","url":null,"abstract":"<p><p>Blood DNA methylation patterns are highly predictive of prenatal exposure to smoking, and differential methylation has been associated with maternal alcohol use. We extended this to determine whether DNA methylation patterns in cord blood are associated with prenatal exposure to opioids, cannabis, and polysubstance use. We also evaluated whether DNA methylation patterns have predictive utility. We examined 932 mother-child pairs in the Boston Birth Cohort between 1998 and 2020 with cord blood DNA methylation data. For each substance self-reported within 72 hr after birth, we performed an adjusted linear regression analysis at 865,859 CpG sites to identify related methylation differences. We generated polyepigenetic scores using summary statistics for each exposure and assessed predictive ability using cross-validation and receiver operating characteristic curves. Specificity of methylation associations was evaluated by assessing overlap across exposure summary statistics and using logistic regression for methylation scores, adjusted for concurrent use. We identified methylation changes at 72, 21, and 1 CpG suggestively associated with prenatal exposure to opioids, cannabis, and polysubstance use, respectively (<i>p</i> < 1e-6), in cord blood, reported for the first time for these exposures. We identified two loci associated at epigenome-wide significance with opioids and one with polysubstance use (<i>p</i> < 1e-8). Methylation scores were highly predictive and exposure-specific, with area under the curve accuracy of 91% for opioids, 90% for cannabis, and 93%-98% depending on polysubstance number. These CpGs provide biologic insights for reducing the impact of substance exposure, and these findings may serve as a biomarker of prenatal substance exposure for future studies and potential clinical utility.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2670885"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A relative methylation ordering biomarker of lactylation-related genes predicts prognosis and therapeutic response in cutaneous melanoma.","authors":"Jiayi Ruan, Lingli Wang, Fukang Liu, Yunlong He, Hongdong Li, Guini Hong","doi":"10.1080/15592294.2026.2670909","DOIUrl":"10.1080/15592294.2026.2670909","url":null,"abstract":"<p><p>Cutaneous melanoma (CM) is highly invasive with limited prognostic tools, and the prognostic relevance of lactylation, a novel post-translational modification, remains unexplored. We developed a lactylation-related prognostic model using relative methylation orderings from The Cancer Genome Atlas (TCGA) melanoma cohort (<i>n</i> = 458), which was validated in two dependent cohorts (<i>n</i> = 241). Comprehensive analyses of immune infiltration, therapy efficacy, drug sensitivity, and tumour mutation burden were conducted between high- and low-risk groups. Results showed that 284 lactylation-related genes collected classified TCGA melanoma patients into two clusters with significant survival differences (Kaplan-Meier log-rank test, <i>p</i> = 0.046). Between the two clusters, 279 differentially methylated loci were identified (false discovery rate < 0.05 and |Δβ| >0.1). Based on these loci, 1,743 locus pairs were significantly associated with overall survival (Univariate Cox regression, false discovery rate < 0.05). From these significant pairs, the CM 11 locus-pair prognostic model (CM-LP11) consisting of 11 pairs was constructed, which could effectively stratify patients into high- and low-risk groups with significantly different overall survival across all datasets (all <i>p</i> < 0.05, log-rank test). The high-risk group exhibited an immunosuppressive microenvironment with reduced CD8+ T cells and B cells and increased monocytes (<i>p</i> < 0.05, Wilcoxon test). Functional analysis of methylation differences between risk groups showed significant immune response-related pathways such as antigen processing and presentation. The high- and low-risk patients also exhibited distinct sensitivity to cytotoxic chemotherapy, targeted therapy, and immunotherapy, with the low-risk group showing higher immunophenoscore, cytolytic activity, and tumor mutational burden. CM-LP11 represents a robust lactylation-related prognostic biomarker that predictive survival outcomes and therapeutic responses in CM patients, proving insights for personalized treatment strategies.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2670909"},"PeriodicalIF":3.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13170386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}