Clinical Epigenetics最新文献

{"title":"Cross-sectional and longitudinal association of seven DNAm-based predictors with metabolic syndrome and type 2 diabetes.","authors":"Suet Mei Chew, Alexander Teumer, Pamela R Matías-García, Christian Gieger, Juliane Winckelmann, Karsten Suhre, Christian Herder, Wolfgang Rathmann, Annette Peters, Melanie Waldenberger","doi":"10.1186/s13148-025-01862-8","DOIUrl":"https://doi.org/10.1186/s13148-025-01862-8","url":null,"abstract":"<p><strong>Background: </strong>To date, various epigenetic clocks have been constructed to estimate biological age, most commonly using DNA methylation (DNAm). These include \"first-generation\" clocks such as DNAmAgeHorvath and \"second-generation\" clocks such as DNAmPhenoAge and DNAmGrimAge. The divergence of one's predicted DNAm age from chronological age, termed DNAmAge acceleration (AA), has been linked to mortality and various aging-related conditions, albeit with varying findings. In metabolic syndrome (MetS) and type 2 diabetes (T2D), it remains inconclusive which DNAm-based predictor(s) is/are closely related to these two metabolic conditions. Therefore, we examined the cross-sectional associations between seven DNAm-based predictors and prevalent metabolic conditions in participants with methylation data from the KORA study. We also analyzed the longitudinal association with time-to-incident T2D and the relative prognostic value compared to clinical predictors from the Framingham 8-year T2D risk function in predicting incident disease over eight years.</p><p><strong>Results: </strong>GrimAA and PhenoAA difference demonstrated consistently significant associations in the cross-sectional and longitudinal analyses. GrimAA difference reported a larger effect: with prevalent MetS at F4 (odds ratio = 1.09, 95% confidence interval = [1.06-1.13], p = 2.04E-08), with prevalent T2D at F4 (odds ratio = 1.09 [1.04-1.13], p = 1.38E-04) and with time-to-incident T2D (hazards ratio = 1.05 [1.01-1.10], p = 0.02) for each year increase in GrimAA difference. Mortality risk score was significantly associated with both prevalent metabolic conditions but not in the longitudinal analysis. The inclusion of DNAm-based predictor in the model with Framingham clinical predictors improved discriminative ability, albeit not significantly. Notably, the DNAm-based predictor, when fitted separately, showed a discriminative ability comparable to that of the model with clinical predictors. Overall, no clear pattern of significant associations was identified in the epigenetic measures from the \"first-generation\" clocks.</p><p><strong>Conclusions: </strong>GrimAA, PhenoAA difference and mortality risk score, derived from the \"second-generation\" clocks, demonstrated significant associations with both MetS and T2D. These DNAm-based predictors may be useful biomarkers for risk stratification and disease prognosis in our study sample of European ancestry. Further research is warranted to investigate the generalizability of our findings across different ancestries and to examine the underlying shared biological mechanisms.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"58"},"PeriodicalIF":4.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810715","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":"Targeting the epigenetic regulation of ferroptosis: a potential therapeutic approach for sepsis-associated acute kidney injury.","authors":"Yuhang Yang, Xinqi Deng, Wenyuan Li, Yan Leng, Yonghong Xiong, Bihan Wang, Siyuan Gong, Yunhao Wang, Baichuan Yang, Wei Li","doi":"10.1186/s13148-025-01861-9","DOIUrl":"10.1186/s13148-025-01861-9","url":null,"abstract":"<p><p>Sepsis is a syndrome of organ dysfunction caused by the invasion of pathogenic microorganisms. In clinical practice, patients with sepsis are prone to concurrent acute kidney injury, which has high morbidity and mortality rates. Thus, understanding the pathogenesis of sepsis-associated acute kidney injury is of significant clinical importance. Ferroptosis is an iron-dependent programmed cell death pathway, which is proved to play a critical role in the process of sepsis-associated acute kidney injury through various mechanisms. Epigenetic regulation modulates the content and function of nucleic acids and proteins within cells through various modifications. Its impact on ferroptosis has garnered increasing attention; however, the role of epigenetic regulation targeting ferroptosis in sepsis-associated acute kidney injury has not been fully elucidated. Growing evidence suggests that epigenetic regulation can modulate ferroptosis through complex pathway networks, thereby affecting the development and prognosis of sepsis-associated acute kidney injury. This paper summarizes the impact of ferroptosis on sepsis-associated acute kidney injury and the regulatory mechanisms of epigenetic regulation on ferroptosis, providing new insights for the targeted therapy of sepsis-associated acute kidney injury.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"57"},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794732","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":"Comparative performance evaluation of bisulfite- and enzyme-based DNA conversion methods.","authors":"Roy B Simons, Faidra Karkala, Marta M Kukk, Hieab H H Adams, Manfred Kayser, Athina Vidaki","doi":"10.1186/s13148-025-01855-7","DOIUrl":"10.1186/s13148-025-01855-7","url":null,"abstract":"<p><strong>Background: </strong>Bisulfite conversion (BC) has been the gold standard in DNA methylation profiling for decades. During this chemical process, non-methylated cytosines are converted into uracils, while methylated cytosines remain intact. Despite its popularity, BC has major drawbacks when used for sensitive applications with low-quality and -quantity DNA samples, such as the required large amount of DNA input, the caused DNA fragmentation and loss, and the resulting reduced sequence complexity. Lately, to account for BC-related disadvantages the first commercial enzymatic conversion (EC) kit was launched. While EC follows the same conversion principle as BC it uses two enzymatic steps instead of one chemical step with BC. In this study, we validated and compared the conversion performance of the most widely used BC and EC kits using a multiplex qPCR assay (qBiCo) we recently developed, which provides several indexes: conversion efficiency, converted DNA recovery and fragmentation.</p><p><strong>Results: </strong>Firstly, we implemented and standardized both DNA conversion methods. Secondly, using qBiCo, we performed a developmental validation for both conversion approaches, including testing the following parameters: repeatability, reproducibility, sensitivity and robustness. Regarding conversion efficiency, both methods performed similarly, with the limit of reproducible conversion being 5 ng and 10 ng for BC and EC, respectively. The recovery, however, is structurally overestimated for BC: 2.3 ± 0.7 and 0.7 ± 0.2 for EC. In contrast, degraded DNA input resulted in high fragmentation values after BC and low-medium values for EC (14.4 ± 1.2 and 3.3 ± 0.4, respectively). Finally, we converted 10 ng of 22 genomic DNA samples using both methods. We observed an overestimation of the BC DNA recovery (130%) and a low recovery for EC (40%).</p><p><strong>Conclusions: </strong>Our findings indicate that both DNA conversion methods have strengths and weaknesses. BC shows a high recovery, whereas EC does not cause extensive fragmentation that is characteristic to BC. EC is, therefore, more robust to the analysis of degraded DNA such as forensic-type or cell-free DNA, at least for the genomic DNA inputs tested here. We believe that the low recovery of EC could be improved by further optimizing and automating the bead-based cleanup steps. Overall, our study provides the first independent benchmarking of bisulfite- and enzyme-based conversion kits.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"56"},"PeriodicalIF":4.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779280","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":"Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants.","authors":"Yao Hu, Jeff Haessler, Jessica I Lundin, Burcu F Darst, Eric A Whitsel, Megan Grove, Weihua Guan, Rui Xia, Mindy Szeto, Laura M Raffield, Scott Ratliff, Yuxuan Wang, Xuzhi Wang, Alison E Fohner, Megan T Lynch, Yesha M Patel, S Lani Park, Huichun Xu, Braxton D Mitchell, Joshua C Bis, Nona Sotoodehnia, Jennifer A Brody, Bruce M Psaty, Gina M Peloso, Michael Y Tsai, Stephen S Rich, Jerome I Rotter, Jennifer A Smith, Sharon L R Kardia, Alex P Reiner, Leslie Lange, Myriam Fornage, James S Pankow, Mariaelisa Graff, Kari E North, Charles Kooperberg, Ulrike Peters","doi":"10.1186/s13148-025-01859-3","DOIUrl":"10.1186/s13148-025-01859-3","url":null,"abstract":"<p><p>Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"54"},"PeriodicalIF":4.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771408","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":"Sleep disturbances, shift work, and epigenetic ageing in working-age adults: findings from the Young Finns study.","authors":"Ida Autio, Aino Saarinen, Saara Marttila, Emma Raitoharju, Pashupati P Mishra, Nina Mononen, Mika Kähönen, Liisa Keltikangas-Järvinen, Olli Raitakari, Terho Lehtimäki","doi":"10.1186/s13148-025-01860-w","DOIUrl":"10.1186/s13148-025-01860-w","url":null,"abstract":"<p><strong>Background: </strong>Sleep disturbances are known to have adverse effects on health, but knowledge on the effect of sleep disturbances on epigenetic ageing is limited. We investigated (1) whether symptoms of insomnia, obstructive sleep apnoea, sleep deprivation, and circadian rhythm lateness are associated with epigenetic ageing, and (2) whether years spent in shift work moderates these associations.</p><p><strong>Methods: </strong>We used the population-based Young Finns data (n = 1618). Epigenetic clocks such as AgeDev_Hannum, AgeDev_Horvath, AgeDev_Pheno, AgeDev_Grim, and DunedinPACE were utilized to measure epigenetic ageing. Sleep was evaluated using various validated self-report questionnaires. Covariates included sex, array type, smoking status, health behaviours, socioeconomic factors, and cardiovascular health factors.</p><p><strong>Results: </strong>Among the various sleep measures, obstructive sleep apnoea symptoms were most consistently linked to accelerated epigenetic ageing, as measured by AgeDev_Grim and DunedinPACE. Insomnia, sleep deprivation, and years spent in shift work were not associated with epigenetic ageing after adjusting for health-related or socioeconomic covariates. Additionally, we found interactions between years spent in shift work and sleep disturbances when accounting for epigenetic ageing. Among those with little to no history of shift work, both insomnia and sleep deprivation were associated with more accelerated epigenetic ageing in AgeDev_Grim when compared to long-term shift workers. However, the pace of epigenetic ageing (measured with DunedinPACE) appears to be higher in those with both sleep deprivation and longer history of shift work.</p><p><strong>Conclusions: </strong>Among various sleep measures, symptoms of obstructive sleep apnoea appear to be most consistently associated with accelerated epigenetic ageing even after adjusting for various health-related and socioeconomic factors. Shift work seems to have a crucial role in the relationship between sleep disturbances and epigenetic ageing in working-age adults.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"55"},"PeriodicalIF":4.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771411","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":"Correction: Respiratory infection‑ and asthma‑prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.","authors":"David Martino, Nikki Schultz, Ravinder Kaur, Simon D van Haren, Nina Kresoje, Annmarie Hoch, Joann Diray-Arce, Jessica Lasky Su, Ofer Levy, Michael Pichichero","doi":"10.1186/s13148-025-01848-6","DOIUrl":"https://doi.org/10.1186/s13148-025-01848-6","url":null,"abstract":"","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"53"},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742479","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 effect of 1,25(OH)₂D₃ on Dickkopf-1 methylation in colorectal cancer.","authors":"Hongyan Sun, Liehao Yang, Nan Li, Yue Hu, Qianying Hu, Zilong Zhou, Xianling Cong","doi":"10.1186/s13148-025-01857-5","DOIUrl":"10.1186/s13148-025-01857-5","url":null,"abstract":"<p><strong>Background: </strong>Vitamin D is a fat-soluble vitamin that has a protective role in colorectal cancer. Several studies have identified the association between vitamin D and changes in DNA methylation in different types of tumours. Dickkopf-1 (DKK1) inhibits the Wnt/β-catenin signalling pathway, and 1,25(OH)₂D₃ can induce DKK1 expression in colorectal cancer. However, whether 1,25(OH)₂D₃ can affect DKK1 expression by regulating DNA methylation in colorectal cancer is not known.</p><p><strong>Methods: </strong>Fifty-seven colorectal cancer (CRC) patients and fifty-five healthy controls were included in this study. Serum DKK1 and 25(OH)D levels were measured via ELISA and liquid chromatography‒tandem mass spectrometry, respectively, and the associations of DKK1 with clinicopathological characteristics and 25(OH)D were analysed. A DKK1 expression plasmid was transfected into cells to assess the functional significance of DKK1 in CRC progression via CCK8, wound healing and migration assays. BiSulphite Amplicon Sequencing (BSAS) and methylation-specific PCR were used to detect the DKK1 methylation status of colorectal cancer cells and tissues. The effect of 1,25(OH)₂D₃ on DKK1 methylation was investigated by pyrosequencing. A dual-luciferase reporter assay was performed to investigate the influence of CpG island methylation on DKK1 transcriptional activity.</p><p><strong>Results: </strong>A decreased serum DKK1 level was closely associated with nerve infiltration and 25(OH)D status in patients with colorectal cancer. Overexpression of DKK1 reduced the proliferative and migratory capabilities of colorectal cancer cells. The methylation patterns of DKK1 (- 195 to + 231), including 31 CpG sites, were assayed via BSAS in CRC cells and tissues. Compared with those in adjacent normal tissues, the methylation levels of multiple CpG sites located in the promoter, 5'UTR and exon 1 were increased in tumour tissues. DKK1 hypermethylation was associated with decreased DKK1 expression in colorectal cancer cells and tissues. 1,25(OH)₂D₃ induced DKK1 expression in colorectal cancer cells, and pyrosequencing revealed that 1,25(OH)₂D₃ treatment induced demethylation of CpG sites located in the promoter (- 97 to - 32) and 5'UTR (+ 39 to + 97). The dual-luciferase reporter assay further confirmed that CpG island methylation (-120 to + 225) directly represses DKK1 transcription.</p><p><strong>Conclusion: </strong>DKK1 functions as a tumour suppressor in colorectal cancer, and 1,25(OH)₂D₃ upregulates DKK1 expression by inducing demethylation of the DKK1 promoter and 5'UTR in specific colorectal cancer cell lines.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"52"},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718256","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 regulators combined with tumour immunotherapy: current status and perspectives.","authors":"Huan Zhang, Yutong Pang, Ling Yi, Xiaojue Wang, Panjian Wei, Haichao Wang, Shuye Lin","doi":"10.1186/s13148-025-01856-6","DOIUrl":"10.1186/s13148-025-01856-6","url":null,"abstract":"<p><p>Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"51"},"PeriodicalIF":4.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676738","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 heterogeneity correlates with field cancerization and prognosis in lung adenocarcinoma patients.","authors":"Ying Zhou, Jing Zhang, Yang He, Yun Wang, Bing Li, Tengfei Zhu, Yanjun Su","doi":"10.1186/s13148-025-01845-9","DOIUrl":"10.1186/s13148-025-01845-9","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The distinctive genetic and epigenetic modifications in tumors and paired non-malignant samples, such as adjacent peri-tumor and tumor-distant normal lung tissues, have not been adequately studied.</p><p><strong>Methods: </strong>We recruited 57 patients with resectable stage I-III LUAD and collected matched samples of the primary tumor, peri-tumoral tissues, and tumor-distant normal lung tissue. We performed bisulfite sequencing using a custom methylation panel to profile DNA methylation levels and obtained somatic variation landscape through targeted next-generation sequencing (NGS). We attempted to identify differential methylation blocks (DMBs) between the tumor, peri-tumor, and normal tissues.</p><p><strong>Results: </strong>We analyzed the DNA methylation patterns of matched tumor, peri-tumor, and normal lung tissue samples from 57 LUAD patients. No significantly different methylation blocks were found between peri-tumoral and normal tissues, while they both exhibited distinct methylation profiles compared to tumor tissues. A total of 1329 tumor-specific DMBs, which are potentially associated with aberrant gene expression in LUAD, were identified. Utilizing a consensus clustering algorithm, we classified the tumor samples into two subgroups (C1 and C2) based on distinct methylation profiles, independent of the patient's sex, tumor stage, smoking history, and tumor cell fraction. The C2 subgroup exhibited a higher malignancy density ratio (MD ratio), suggesting a more pronounced degree of field cancerization, while the C1 subgroup was characterized by a higher frequency of EGFR mutations. The DMBs between the two subgroups were enriched in the calcium signaling pathway. Notably, P2RX2 shows significant hypermethylation in the C2 subgroup, and its low expression in the external The Cancer Genome Atlas (TCGA) cohort may correlate with reduced overall survival in LUAD patients.</p><p><strong>Conclusion: </strong>Our findings revealed distinct methylation patterns between tumor and pre-malignant samples, such as peri-tumor and normal tissues. Moreover, our study suggests that distinct clustering based on DNA methylation may indicate different prognoses in LUAD patients.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"50"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669173","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":"Type 2 diabetes impacts DNA methylation in human sperm.","authors":"Lei Su, Jonathan M Dreyfuss, Rafael Ferraz Bannitz, Danielle Wolfs, Georgia Hansbury, Lauren Richardson, Charnice Charmant, Jay Patel, Elizabeth S Ginsburg, Catherine Racowsky, Ruby Fore, Vissarion Efthymiou, Jessica Desmond, Allison Goldfine, Anne Ferguson-Smith, Hui Pan, Marie-France Hivert, Elvira Isganaitis, Mary Elizabeth Patti","doi":"10.1186/s13148-025-01853-9","DOIUrl":"10.1186/s13148-025-01853-9","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Disorders of the reproductive system, including hypogonadism and reduced fertility, are an under-recognized complication of diabetes. Based on experimental data in mice, hyperglycemia and obesity may modify epigenetic marks in sperm and impact health and development of offspring, but data are more limited in humans. Thus, we sought to study the impact of type 2 diabetes and glycemic control on sperm quality and DNA methylation.</p><p><strong>Methods: </strong>In this prospective cohort study, we recruited 40 men with BMI greater than 25 kg/m² including 18 with type 2 diabetes, 6 with prediabetes, and 16 normoglycemic controls. Assessments were repeated after 3 months in 9 men with type 2 diabetes and 7 controls. We analyzed reproductive hormones, sperm concentration and motility, and sperm DNA methylation (MethylationEPIC BeadChip).</p><p><strong>Results: </strong>Men with type 2 diabetes had higher levels of follicle-stimulating hormone (FSH), but similar testosterone levels and sperm quality as controls. Sperm DNA methylation was stable with repeat sampling at 3 months in men with and without type 2 diabetes. We identified differential methylation at 655 of 745,804 CpG sites in men with type 2 diabetes versus controls (FDR < 0.05). Of these, 96.5% showed higher methylation in type 2 diabetes, with a mean difference in DNA methylation (beta value, β) of 0.16 ± 0.004 (16 ± 0.4%). Ontology analysis of differentially methylated loci revealed annotation to genes regulating synaptic signaling, actin, cAMP-dependent pathways, and G protein-coupled receptor pathways. 24% of probes differentially regulated in men with type 2 diabetes versus control overlapped with probes associated with HbA1c, suggesting additional factors beyond glycemic control contributed to diabetes-associated differences in DNA methylation.</p><p><strong>Conclusions/interpretation: </strong>Men with type 2 diabetes showed higher DNA methylation levels in sperm relative to normoglycemic controls with similar BMI. Whether these differences are reversible with glucose-lowering treatment or may contribute to post-fertilization transcriptional regulation warrants further investigation.</p><p><strong>Trial registration: </strong>NCT03860558.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"49"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662932","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}