DNA methylation in peripheral blood is associated with blood lipid levels, but the studies that established these associations were conducted predominantly in European-ancestry populations, and East Asian data remain sparse. Our primary aim was to determine whether established lipid–methylation loci transfer to a Korean population; our secondary aim was to characterize how lipid-specific epigenetic signatures relate to biological aging across clock generations. An epigenome-wide association study (EWAS) of lipid traits (total cholesterol, log-transformed triglyceride [TG], high-density lipoprotein [HDL], and low-density lipoprotein) and hypertriglyceridemia was conducted using peripheral whole-blood leukocyte DNA from 1,527 Korean adults (discovery), with replication in two non-overlapping Korean Genome and Epidemiology Study health examinees (HEXA) subsets (N = 389 and N = 417) profiled on the Illumina EPIC array. Associations with five epigenetic clocks were evaluated. Mediation analysis compared two alternative causal orderings linking epigenetic aging, methylation, and lipids. Robustness was assessed by sensitivity analyses including surrogate variable adjustment, fixed-effect meta-analysis, and methylation risk scores. We identified 1,081 differentially methylated positions associated with logTG (Bacon-corrected false discovery rate < 0.05) and seven associated with HDL. All five CHARGE consortium CpGs (CPT1A, TXNIP, ABCG1, SREBF1, and DHCR24) were confirmed in both replication subsets by meta-analysis (P = 2.2 × 10−3–2.6 × 10–17). Across the wider discovery set, 89.8
Abstract Background 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). Methods 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. Results 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. Conclusion 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.
Glioblastoma (GBM) is a highly malignant brain tumor with an extremely poor prognosis, highlighting the urgent need to identify novel diagnostic and therapeutic targets. Histone acetyltransferase 1 (HAT1) serves as a critical epigenetic regulator. In this study, we systematically investigated the expression characteristics, biological functions, and clinical significance of HAT1 in GBM through multi-omics analysis combined with in vitro and in vivo functional experiments. We found that HAT1 is significantly upregulated in GBM and may act as a promising diagnostic and prognostic biomarker. Functionally, HAT1 maintains genomic stability by facilitating DNA damage repair, cell cycle progression, and metabolic reprogramming, thereby promoting the malignant progression of GBM. Moreover, HAT1 participates in remodeling the tumor immune microenvironment. In vitro, genetic knockdown or pharmacological inhibition of HAT1 markedly suppressed GBM cell proliferation and induced tumor DNA damage. In vivo experiments further validated that HAT1 inhibition effectively impeded GBM tumor growth. Notably, pharmacological inhibition of HAT1 enhances the antitumor efficacy of Temozolomide (TMZ) and Niraparib in GBM cells. In summary, HAT1 is a key epigenetic regulator driving GBM progression, which can serve as a novel prognostic biomarker and a viable therapeutic target for combined treatment strategies, providing new insights for the precise treatment of GBM.
Abstract Context 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. Aim To test whether an exogenous skin ageing epigenetic clock is more strongly associated with aspects of sun-exposure than two endogenous epigenetic clocks. Methods 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. Results 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. Conclusion Skin epigenetic clocks can differentiate exogenous from endogenous skin ageing facilitating further study of the mechanisms underlying these two skin ageing phenomena.
DNA methylation at the 5′ position of cytosine is a classical epigenetic mark in the human genome, and alterations in DNA methylation are frequently observed in cancer. Formalin-fixed, paraffin-embedded (FFPE) tissue is widely used in next-generation sequencing (NGS) for retrospective molecular studies due to preserved tissue architecture and extensive clinically annotated archives. However, fragmented and degraded nucleic acids often limit its utility. Although whole-genome bisulfite sequencing (WGBS) has long been the gold standard for assessing DNA copy-number and methylation, newer enzymatic approaches such as enzymatic-methylation sequencing (EM-seq) and the biomodal duet multiomics solution evoC kit have emerged. Here, we characterized these three methods in FFPE residual triple-negative breast cancer (TNBC) tissue. TNBC is the most aggressive breast cancer subtype, lacks targetable alterations, and is associated with a high risk of local and distant recurrence, with most metastatic progression occurring within three years of diagnosis. Our findings demonstrate the feasibility of applying all three sequencing approaches to low-input FFPE residual TNBC samples and highlight the method-specific trade-offs that should be considered when selecting a sequencing strategy. These findings support a streamlined framework for genetic and epigenetic profiling of archival FFPE residual TNBC samples and future cohort expansion.
