Clinical Epigenetics最新文献

{"title":"ImprintCap, a powerful NGS-based technology to investigate the molecular background of imprinting disorders.","authors":"Frédéric Brioude, Martin A Haagmans, Marcel Mannens, Irene Netchine, Marielle Alders, Peter Henneman, Jet Bliek","doi":"10.1186/s13148-025-01916-x","DOIUrl":"10.1186/s13148-025-01916-x","url":null,"abstract":"<p><strong>Introduction: </strong>Imprinting disorders (IDs) are a rare class of diseases caused by the disruption of imprinted genes, i.e., genes with a specific pattern of expression from only one allele. Currently, 48 loci are known to show parent-of-origin dependent, imprinted, expression in humans, some of which are disease-associated (da) whereas most of them are non-disease-associated (nda) loci. A subset of patients with an imprinting disorder exhibits aberrant imprinting in at least one differentially methylated region (DMR) in addition to the da loci. Correlation between multilocus imprinting disturbance (MLID), phenotype, variants in maternal effect proteins and fertility problems are currently under investigation. There is a need for a reliable, cost-effective method to detect low mosaic levels of methylation changes in all DMRs. To this end, a targeted NGS panel named ImprintCap was developed using the TWIST method for 48 DMRs. To validate the technique, 13 patients with known methylation changes were analyzed, and these were compared to 30 control samples.</p><p><strong>Results: </strong>Methylation ranges of mean + / - 3SD were determined in 41/48 DMRs in the capture, including all da DMRs. The mean relative coverage was used to detect CNVs in each DMR. The diagnostic findings were confirmed using ImprintCap in all patients' samples, including methylation changes and deletions. From four samples with genome-wide uniparental disomy (UPD), we determined a detection level of at least 30% mosaic aberrant cells. Three patients were known to show MLID in one or more da DMRs. These changes were confirmed, and in addition, methylation changes were found in 17-32 da or nda DMRs.</p><p><strong>Conclusion: </strong>By employing ImprintCap, methylation changes can be detected in 41 DMRs, with an overall detection level of 30% mosaic. The DMRs are located on 20 different chromosomes, enabling the detection of UPD in these regions, in addition to CNV in DMRs. The combination of these characteristics renders the methods highly suitable as a diagnostic test for all IDs, detecting UPD, methylation changes and CNVs. The panel is also a reliable tool for the detection of MLID involving both da and nda DMRs.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"119"},"PeriodicalIF":4.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583254","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":"Decitabine regulates the resistance of HCC to sorafenib through demethylation.","authors":"Miao Zhang, Xiaolei Zhou, Zhenzhen Li, TianYu Zhao, Yu Miao, Sen Liu, Qiaoqiao Han, Libo Wang, Yongdeng Xu, Tao Cui, Ze Wang, Xiulin Yi, Fengying Yan, Xiaoliang Wang","doi":"10.1186/s13148-025-01925-w","DOIUrl":"10.1186/s13148-025-01925-w","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the efficacy of sorafenib in combination with the DNA methylation inhibitor decitabine (DAC) for the treatment of hepatocellular carcinoma (HCC), and to investigate the mechanism of sorafenib resistance from an epigenetic perspective, aiming to provide new insights and strategies for HCC therapy.</p><p><strong>Methods: </strong>The GEPIA2 database was used to analyze the expression of solute carrier organic anion transporter family member 1B3 (SLCO1B3) in various tumors and adjacent normal tissues. The Kaplan-Meier method was applied to assess the relationship between SLCO1B3 expression and overall survival. The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) dataset was used to analyze correlations between SLCO1B3 and DNA methyltransferases (DNMTs). Methylation levels of the SLCO1B3 promoter in Hep3B, HepG2, SNU182, and SNU387 cells were determined by bisulfite sequencing PCR. The expression of organic anion transporting polypeptide 1B3 (OATP1B3), encoded by SLCO1B3, was measured by RT-qPCR and Western blot. The effect of sorafenib combined with DAC on Hep3B and HepG2 cells proliferation was dynamically monitored using the Agilent xCELLigence Real-Time Cell Analysis eSight system (RTCA-eSight). The mechanism was further validated in vivo using a Hep3B xenograft model in nude mice. OATP1B3 expression in tumor tissues was examined by immunohistochemistry and Western blot.</p><p><strong>Results: </strong>HCC patients with high SLCO1B3 expression had significantly better overall survival than those with low expression. SLCO1B3 expression was negatively correlated with DNMTs expression. Compared to other HCC cell lines, Hep3B and HepG2 cells exhibited higher DNA methylation levels and lower OATP1B3 protein expression. DAC treatment upregulated OATP1B3 expression in Hep3B and HepG2 cells. Co-administration of DAC increased sorafenib uptake and enhanced its cytotoxic effect in these cells. In the Hep3B xenograft model, tumor volumes in the combination group were markedly smaller than those in the monotherapy and control groups. OATP1B3 expression was significantly higher in both the combination and DAC-only groups compared to the control and sorafenib-only groups.</p><p><strong>Conclusion: </strong>DAC promoted OATP1B3 expression by inhibiting SLCO1B3 methylation, thereby enhancing HCC sensitivity to sorafenib. These findings may offer novel therapeutic strategies for the clinical management of HCC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"120"},"PeriodicalIF":4.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583253","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 age acceleration and allergic diseases: a bidirectional two-sample Mendelian randomization study.","authors":"Junfang Sun, Guozhen Fan, Lixin Hu, Zheng Hai Qu, Hong Jiang","doi":"10.1186/s13148-025-01927-8","DOIUrl":"10.1186/s13148-025-01927-8","url":null,"abstract":"<p><strong>Objective: </strong>The epigenetic clock has been regarded as a highly accurate predictor of capturing the complexity between aging and the epigenome. However, there is limited understanding of the epigenetic clock in allergic diseases. The aim of this study was to explore the causal relationship between epigenetic age acceleration and allergic diseases by conducting a bidirectional two-sample Mendelian randomization (MR) study.</p><p><strong>Methods: </strong>Pleiotropy analysis was conducted using the MR-Egger intercept test and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test. Instrumental variables were constructed using single nucleotide polymorphisms. The statistics for epigenetic age acceleration and allergic diseases were derived from genome-wide association studies (GWAS) of European ancestry. MR analysis was performed using inverse variance weighted, weighted median, and MR-Egger methods.</p><p><strong>Results: </strong>Based on the inverse variance weighted method, the forward MR analysis showed that intrinsic epigenetic age acceleration (IEAA) was associated with an increased risk of allergic asthma (OR = 1.051, 95% CI 1.006 to 1.098, p = 0.025). The reverse MR analysis also indicated a significant causal relationship between allergic asthma and IEAA (OR = 1.410, 95% CI 1.111 to 1.791, p = 0.005). However, there was a lack of evidence supporting a causal relationship between IEAA and allergic conjunctivitis, atopic dermatitis, allergic rhinitis and allergic urticaria (all p > 0.05). Quality control assessments demonstrated that our study results were reliable and robust.</p><p><strong>Conclusions: </strong>This study revealed bidirectional causal relationships between intrinsic epigenetic age acceleration and allergic asthma, highlighting potential prevention strategies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"117"},"PeriodicalIF":4.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567199","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 regulation of TNNT1 in gastrointestinal cancers prognostic implications and clinical significance.","authors":"Jin Xie, Xin-Yang Qu, Rui-Min Wu, Jie Liu, Fan Cheng, Yu Zhang, Xu-Sheng Liu","doi":"10.1186/s13148-025-01928-7","DOIUrl":"10.1186/s13148-025-01928-7","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to investigate the expression profile and clinical significance of the Troponin T Type 1 (TNNT1) gene across various digestive system tumors. By elucidating the role of TNNT1 in tumor progression, we hope to establish its potential as a prognostic biomarker and therapeutic target.</p><p><strong>Methods: </strong>We assessed the expression levels of TNNT1 by employing bioinformatics analyses, including differential gene expression analysis and survival analysis utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The impact of TNNT1 expression on patient prognosis was evaluated through Cox regression analyses. Furthermore, functional enrichment analysis was conducted to explore the biological pathways involved, alongside promoter methylation and mutation analyses, to elucidate its regulatory mechanisms. TNNT1 protein levels were analyzed through immunohistochemistry (IHC) on tissue microarray (TMA) sections.</p><p><strong>Results: </strong>Our findings demonstrate that TNNT1 is significantly overexpressed in tumor tissues compared to normal tissues, with elevated expression levels correlating with poor prognosis specifically in colon adenocarcinoma (COAD), liver hepatocellular carcinoma and pancreatic adenocarcinoma. Functional analyses indicated that TNNT1 is involved in tumor aggressiveness-related processes such as epidermal development and keratinization. Notably, TNNT1 expression was linked to immune cell infiltration patterns, highlighting its potential role in modulating the tumor immune microenvironment. IHC analysis revealed significantly higher TNNT1 levels in COAD and rectum adenocarcinoma tissues compared to control samples.</p><p><strong>Conclusion: </strong>This study underscores the potential of TNNT1 as a prognostic biomarker and therapeutic target in digestive system tumors. Our findings pave the way for future research aimed at elucidating the intricate mechanisms underlying TNNT1's roles in tumor biology and its therapeutic implications in improving patient outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"115"},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564551","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 and hydroxymethylation combined with transcriptional profiling identify key regulators of hyperoxia-induced bronchopulmonary dysplasia.","authors":"Hui-Tao Li, Tao Qian, Hao-Min Zhang, Qiu-Hua Li, Yi-Yun Ma, Yi-Fan Li, Zi-Lu Huang, Dong-Shan Han, Yuan-Ye Dang, Ying-Ying Xiao, Ling Sun, Xue-Yu Chen, Xue-Yan Jiang","doi":"10.1186/s13148-025-01926-9","DOIUrl":"10.1186/s13148-025-01926-9","url":null,"abstract":"<p><strong>Background: </strong>Hyperoxia-induced bronchopulmonary dysplasia (BPD) is a major cause of lung injury in premature infants. Epigenetics, particularly DNA (hydroxy)methylation, has been identified as a crucial regulator of BPD pathogenesis. This study aimed to reveal key regulators and pathogenic genes involved in hyperoxia-induced BPD via DNA (hydroxy)methylation and transcriptional analysis.</p><p><strong>Methods and results: </strong>Multi-omics analyses including RNA-seq, reduced representation bisulfite sequencing (RRBS), and oxidative RRBS (oxRRBS) were conducted on lung tissues from hyperoxia-induced rat BPD model. Differentially methylated and hydroxymethylated regions (DMRs and DhMRs) were further detected by targeted bisulfite sequencing (TBS) and oxidative TBS (oxTBS). Differentially expressed genes (DEGs) were finally verified in hyperoxia-exposed lung tissues by qPCR, western blotting, and immunohistochemistry. Our integrated analysis identified 2058 DEGs, 62,123 DMRs, and 33,212 DhMRs in hyperoxia-induced BPD. Among them, eighteen candidate genes with altered expression patterns were revealed to be involved in BPD-related pathways. Notably, ten candidate genes, including Cxcl6, Gpr39, Hs6st2, Htatip2, Apln, Calca, Hist1h1t, Lgals3, Rarres1, and Rasl2-9, exhibited significant upregulation with both hypo-DNA methylation and hyper-DNA hydroxymethylation levels. Conversely, eight candidate genes, containing Krt76, Spon2, Abcc6, Egfl7, Gpbar1, Myh6, Tgfbi, and Tmem100, displayed pronounced downregulation associated with both hyper-DNA methylation and hypo-DNA hydroxymethylation levels. Most importantly, the upregulation of Apln and Calca was further validated in hyperoxia-induced BPD, which was characterized by reduced DNA methylation and increased DNA hydroxymethylation levels at their promoter regions.</p><p><strong>Conclusions: </strong>This study reveals that hyperoxia triggers decreased DNA methylation together with increased DNA hydroxymethylation at promoter regions of Apln and Calca, promoting their gene expression and contributing to BPD pathogenesis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"116"},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564550","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":"Methylation-based smoking signatures in blood and tissue samples for the prediction of self-reported smoking status and mortality in patients with colorectal cancer.","authors":"Tanwei Yuan, Katrin E Tagscherer, Wilfried Roth, Melanie Bewerunge-Hudler, Alexander Brobeil, Matthias Kloor, Hendrik Bläker, Hermann Brenner, Michael Hoffmeister","doi":"10.1186/s13148-025-01918-9","DOIUrl":"10.1186/s13148-025-01918-9","url":null,"abstract":"<p><strong>Background: </strong>Smoking is a well-established risk factor for colorectal cancer (CRC) development. However, the reliability of DNA methylation-based smoking signatures in predicting smoking status and their prognostic value in CRC remain unclear, particularly across different biological sample types.</p><p><strong>Results: </strong>Five previously validated methylation-based smoking signatures were analyzed in 2237 CRC patients with blood-derived DNA and 2273 patients with tumor tissue-derived DNA. Blood-derived signatures showed strong correlations with self-reported smoking status, effectively differentiating current smokers from never smokers (all p < 0.0001), with excellent discriminative ability (median area under the receiver operating characteristic curve: 0.94). In contrast, tumor tissue-derived signatures exhibited much weaker associations with smoking status. Among non-metastatic CRC patients, blood-derived methylation signatures were significantly associated with increased risks of all-cause and non-CRC-related mortality, but not with CRC-specific mortality. Conversely, two tumor tissue-derived signatures demonstrated stronger associations with CRC-specific mortality compared to blood-derived signatures.</p><p><strong>Conclusions: </strong>Blood-derived methylation-based smoking signatures are robust indicators for smoking exposure and are associated with increased mortality risk among non-metastatic CRC patients. When applied to tumor tissue, signatures showed stronger associations with CRC-specific mortality.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"113"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559409","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":"Exposing the DNA methylation-responsive compartment of the leukaemic genome in T-ALL cell lines support its potential as a novel therapeutic target in T-ALL.","authors":"Maike Bensberg, Aida Selimović-Pašić, Lisa Haglund, Júlia Goldmann, Sandra Hellberg, Colm E Nestor","doi":"10.1186/s13148-025-01915-y","DOIUrl":"10.1186/s13148-025-01915-y","url":null,"abstract":"<p><p>T-cell acute lymphoblastic leukaemia (T-ALL) exhibits exceptionally high levels of DNA methylation, with silencing of the DNA demethylating enzyme TET2 implicated in T-ALL's hypermethylation phenotype. We propose that DNA hypomethylating agents (HMAs) could be particularly potent in T-ALL cells with this phenotype. Here, we used a reversible DNMT1-specific inhibitor and the conventional HMAs, 5-azacytidine and decitabine, to assess the effects of global DNA methylation loss in T-ALL cell lines and the potential of using HMAs as targeted therapeutic agents in T-ALL. We demonstrate that removal of DNA methylation, even in the absence of DNA damage, results in cell death and that toxicity is negatively correlated with methylation levels. Notably, whereas DNA demethylation caused limited transcriptional changes, key tumour suppressor genes, including TET2, were upregulated in a methylation-dependent manner. Few endogenous retroviruses or immune-related genes were reactivated after demethylation, challenging the contribution of 'viral mimicry' to HMA toxicity. Together, these findings provide fundamental insights into the role of DNA methylation in T-ALL, demonstrating that the removal of DNA methylation alone is sufficient to (i) induce cell death in T-ALL cell lines and (ii) reactivate silenced tumour suppressor genes. Our findings support the development of therapies targeting the unique methylation phenotype of T-ALL.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"114"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559408","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 age acceleration and rheumatoid arthritis: an NHANES-based analysis and survival prediction models.","authors":"Yuhang Ou, Zhihao Wang, Yunbo Yuan, Yuze He, Wenhao Li, Hao Ren, Junhong Li, Siliang Chen, Yanhui Liu","doi":"10.1186/s13148-025-01919-8","DOIUrl":"10.1186/s13148-025-01919-8","url":null,"abstract":"<p><strong>Objective: </strong>Epigenetic aging has been confirmed to be associated with the pathogenesis of rheumatoid arthritis (RA), however, its role in the prognosis of RA remains unclear.</p><p><strong>Methods: </strong>In this cross-sectional and prospective study, Epigenetic age and acceleration in participants of the National Health and Nutrition Examination Survey (NHANES) were calculated with Horvath's clock, Hannum's clock, PhenoAge, GrimAge, and GrimAge version 2 (GrimAge2). The association of epigenetic age and epigenetic age acceleration with the prevalence and overall mortality risk in RA was assessed with prediction models constructed.</p><p><strong>Results: </strong>Accelerated epigenetic aging increased the risk of overall mortality in RA with hazard ratio of 1.075 (95% CI 1.043-1.107, p < 0.0001) for GrimAge2 acceleration (GrimAge2Accel) and 1.064 (1.032-1.098, p < 0.0001) for GrimAge acceleration (GrimAgeAccel). The GrimAge2Accel-based models, adjusted for a set of covariates composed of independent risk factors, excelled in predicting the 10 year and 20 year survival with area under curve of 0.760 (95% CI 0.621-0.898) and 0.823 (0.697-0.949), respectively.</p><p><strong>Conclusion: </strong>Epigenetic aging may play a harmfully promotive role in the onset and progression of RA, and the GrimAge2Accel-based prediction models could effectively predict the survival of RA patients. Further research is needed to elucidate the underlying mechanisms and to explore the potential clinical implications.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"111"},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552426","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":"Newborn mitochondrial DNA copy number is associated with changes to DNA methylation that persist into childhood and are associated with cognitive development.","authors":"Allison Kupsco, Jonathan A Heiss, Marco Sanchez-Guerra, Guadalupe Estrada-Gutierrez, Corina Lesseur, Carmen Hernández, Tessa R Bloomquist, Gaylord Abigail, Jia Guo, Shuang Wang, Julie B Herbstman, Allan C Just, Martha M Téllez-Rojo, Robert O Wright, Andrea A Baccarelli","doi":"10.1186/s13148-025-01896-y","DOIUrl":"10.1186/s13148-025-01896-y","url":null,"abstract":"<p><strong>Background/objectives: </strong>Mitochondrial-nuclear crosstalk is critical for cell function, and nuclear DNA methylation (DNAm) may regulate this process. Mitochondria maintain an extranuclear genome, and mitochondrial DNA copy number (mtDNA-CN) has been previously associated with DNAm. However, there is little information on this relationship in children, whose brains are particularly vulnerable to energetic perturbations during development. Our objectives were to (1) characterize associations of mtDNA-CN with nuclear DNAm at birth; (2) determine their persistence into childhood; and (3) investigate associations in relation to neurodevelopment.</p><p><strong>Methods: </strong>We quantified mtDNA-CN with qRT-PCR and DNAm with the MethylationEPIC BeadChip array in umbilical cord leukocytes (N = 422) in newborns from the PROGRESS birth cohort in Mexico City (2007-2011). At the 48-month visit, we measured DNAm in peripheral blood leukocytes (N = 177) and assessed the McCarthy Scales of Children's Abilities (N = 290). We performed an epigenome-wide association study (EWAS) with cord mtDNA-CN in mitochondrially relevant genes (23,261 CpG sites) and across the genome (745,691 sites). We determined if our results persisted until childhood and were associated with cognitive scales. The findings were replicated in a US-based cohort (N = 130).</p><p><strong>Results: </strong>We observed 11 and 165 differentially methylated positions (DMPs) in mitochondria-related nuclear genes and across the genome, respectively, after correction for multiple comparisons. In mitochondrial genes, two significant DMPs mapped to PRELID3A and a DMP in the promoter region of SLC25A24 replicated in our external cohort. At 48 months of age, 17 of 165 DMPs remained associated with cord mtDNA-CN, 12 were associated with child memory scales, and associations with 17 replicated in our external cohort. Several positions mapped to genes in immune activation and development.</p><p><strong>Conclusions: </strong>In newborns, mtDNA-CN was associated with DNAm in mitochondria-related genes and throughout the genome, several of which remained associated in childhood, were associated with child memory scales, and were replicated in a US-based cohort. These findings open new avenues for future targets for children's health and disease.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"112"},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552428","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":"A review of the use of tumour DNA methylation for breast cancer subtyping and prediction of outcomes.","authors":"Elaheh Zarean, Shuai Li, Melissa C Southey, Pierre-Antoine Dugué","doi":"10.1186/s13148-025-01922-z","DOIUrl":"10.1186/s13148-025-01922-z","url":null,"abstract":"<p><p>DNA methylation in breast tumours has been extensively studied and has provided valuable insights into the clinical heterogeneity of breast cancer. In this review, we summarise the current literature that has used DNA methylation markers to subtype breast cancer and predict progression and survival. Widespread methylation differences have been observed across breast cancer subtypes at both the candidate genes and in genome-wide analyses, most notably between oestrogen receptor (ER) positive and ER-negative subtypes and for triple-negative tumours. Studies that attempted to create breast cancer subtypes using methylation data showed limited agreement in their capacity to group breast tumours, possibly due to methodological differences. Although many studies have reported associations of tumour DNA methylation with breast cancer outcomes and used machine learning methods to derive prediction models for survival, the extent to which these would replicate in independent datasets is currently unclear. We conclude that despite the potential of genome-wide methylation markers to unravel the heterogeneity of breast cancer, they currently appear to have limited clinical utility. Larger studies and replication of findings across studies are required to address the limitations of the existing literature.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"109"},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552425","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}