Clinical Epigenetics最新文献

{"title":"Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer.","authors":"Weiyu Su, Weiwen Wang, Guanghui Zhang, Lianhe Yang","doi":"10.1186/s13148-025-01852-w","DOIUrl":"10.1186/s13148-025-01852-w","url":null,"abstract":"<p><p>Signal transduction plays a pivotal role in modulating a myriad of critical processes, including the tumour microenvironment (TME), cell cycle arrest, proliferation and apoptosis of tumour cells, as well as their migration, invasion, and the epithelial-mesenchymal transition (EMT). Epigenetic mechanisms are instrumental in the genesis and progression of tumours. The Chromobox (CBX) family proteins, which serve as significant epigenetic regulators, exhibit tumour-specific expression patterns and biological functionalities. These proteins are influenced by a multitude of factors and could modulate the activation of diverse signalling pathways within tumour cells through alterations in epigenetic modifications, thereby acting as either oncogenic agents or tumour suppressors. This review aims to succinctly delineate the composition, structure, function, and expression of CBXs within tumour cells, with an emphasis on synthesizing and deliberating the CBXs-mediated activation of intracellular signalling pathways and the intricate mechanisms governing tumourigenesis and progression. Moreover, a plethora of contemporary studies have substantiated that CBXs might represent a promising target for the diagnosis and therapeutic intervention of tumour patients. We have also compiled and scrutinized the current research landscape concerning inhibitors targeting CBXs, aspiring to aid researchers in gaining a deeper comprehension of the biological roles and mechanisms of CBXs in the malignant evolution of tumours, and to furnish novel perspectives for the innovation of targeted tumour therapeutics.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"48"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623815","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":"SNUH methylation classifier for CNS tumors.","authors":"Kwanghoon Lee, Jaemin Jeon, Jin Woo Park, Suwan Yu, Jae-Kyung Won, Kwangsoo Kim, Chul-Kee Park, Sung-Hye Park","doi":"10.1186/s13148-025-01824-0","DOIUrl":"10.1186/s13148-025-01824-0","url":null,"abstract":"<p><strong>Background: </strong>Methylation profiling of central nervous system (CNS) tumors, pioneered by the German Cancer Research Center, has significantly improved diagnostic accuracy. This study aimed to further enhance the performance of methylation classifiers by leveraging publicly available data and innovative machine-learning techniques.</p><p><strong>Results: </strong>Seoul National University Hospital Methylation Classifier (SNUH-MC) addressed data imbalance using the Synthetic Minority Over-sampling Technique (SMOTE) algorithm and incorporated OpenMax within a Multi-Layer Perceptron to prevent labeling errors in low-confidence diagnoses. Compared to two published CNS tumor methylation classification models (DKFZ-MC: Deutsches Krebsforschungszentrum Methylation Classifier v11b4: RandomForest, 767-MC: Multi-Layer Perceptron), our SNUH-MC showed improved performance in F1-score. For 'Filtered Test Data Set 1,' the SNUH-MC achieved higher F1-micro (0.932) and F1-macro (0.919) scores compared to DKFZ-MC v11b4 (F1-micro: 0.907, F1-macro: 0.627). We evaluated the performance of three classifiers; SNUH-MC, DKFZ-MC v11b4, and DKFZ-MC v12.5, using specific criteria. We set established 'Decisions' categories based on histopathology, clinical information, and next-generation sequencing to assess the classification results. When applied to 193 unknown SNUH methylation data samples, SNUH-MC notably improved diagnosis compared to DKFZ-MC v11b4. Specifically, 17 cases were reclassified as 'Match' and 34 cases as 'Likely Match' when transitioning from DKFZ-MC v11b4 to SNUH-MC. Additionally, SNUH-MC demonstrated similar results to DKFZ-MC v12.5 for 23 cases that were unclassified by v11b4.</p><p><strong>Conclusions: </strong>This study presents SNUH-MC, an innovative methylation-based classification tool that significantly advances the field of neuropathology and bioinformatics. Our classifier incorporates cutting-edge techniques such as the SMOTE and OpenMax resulting in improved diagnostic accuracy and robustness, particularly when dealing with unknown or noisy data.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"47"},"PeriodicalIF":4.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613769","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":"Epigenome-wide association study for dilated cardiomyopathy in left ventricular heart tissue identifies putative gene sets associated with cardiac pathology and early indicators of cardiac risk.","authors":"Konstanze Tan, Darwin Tay, Wilson Tan, Hong Kiat Ng, Eleanor Wong, Michael P Morley, Gurpreet K Singhera, Chang Jie Mick Lee, Pritesh R Jain, Fei Li Tai, Paul J Hanson, Thomas P Cappola, Kenneth B Margulies, Roger Foo, Marie Loh","doi":"10.1186/s13148-025-01854-8","DOIUrl":"10.1186/s13148-025-01854-8","url":null,"abstract":"<p><strong>Background: </strong>Methylation changes linked to dilated cardiomyopathy (DCM) affect cardiac gene expression. We investigate DCM mechanisms regulated by CpG methylation using multi-omics and causal analyses in the largest cohort of left ventricular tissues available.</p><p><strong>Methods: </strong>We mapped DNA methylation at ~ 850,000 CpG sites, performed array-based genotyping and conducted RNA sequencing on left ventricular tissue samples from failing and non-failing hearts across two independent DCM cohorts (discovery n = 329, replication n = 85). Summary-data-based Mendelian Randomisation (SMR) was applied to explore the causal contribution of sentinel CpGs to DCM. Fine-mapping of regions surrounding sentinel CpGs revealed additional signals for cardiovascular disease risk factors. Coordinated changes across multiple CpG sites were examined using weighted gene co-expression network analysis (WGCNA).</p><p><strong>Results: </strong>We identified 194 epigenome-wide significant CpGs associated with DCM (discovery P < 5.96E-08), enriched in active chromatin states in heart tissue. Amongst these, 32 sentinel CpGs significantly influenced the expression of 30 unique proximal genes (± 1 Mb). SMR suggested the causal contribution of two sentinel CpGs to DCM and two other sentinel CpGs to the expression of two unique proximal genes (P < 0.05). For one sentinel CpG, colocalisation analyses provided suggestive evidence for a single causal variant underlying the methylation-gene expression relationship. Fine-mapping revealed additional signals linked to cardiovascular disease-relevant traits, including creatinine levels and the Framingham Risk Score. Co-methylation modules were enriched in gene sets and transcriptional regulators related to cardiac physiological and pathological processes, as well as in transcriptional regulators whose cardiac relevance has yet to be determined.</p><p><strong>Conclusions: </strong>Using the largest series of left ventricular tissue to date, this study investigates the causal role of cardiac methylation changes in DCM and suggests targets for experimental studies to probe DCM pathogenesis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"45"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal epigenetic index links early neglect to later neglectful care and other psychopathological, cognitive, and bonding effects.","authors":"Inmaculada León, Daylín Góngora, María José Rodrigo, Silvia Herrero-Roldán, Maykel López Rodríguez, Colter Mitchell, Jonah Fisher, Yasser Iturria-Medina","doi":"10.1186/s13148-025-01839-7","DOIUrl":"10.1186/s13148-025-01839-7","url":null,"abstract":"<p><strong>Background: </strong>Past experiences of maltreatment and life adversity induce DNA methylation changes in adults, but less is known about their impact on mothers' maladaptive neglectful parenting and its negative effects. We performed an epigenome-wide association study to investigate the role of DNA methylation levels in mothers with neglectful care, who were exposed to childhood maltreatment and neglect, and their current negative effects. Saliva DNA methylation was determined with the Illumina Human Methylation EPIC BeadChip v1. The individual epigenome was the input to a machine learning algorithm for trajectory inference, which assigned a specific state to each mother in the progression from healthy controls to the extreme neglect condition. A compound epigenetic maternal neglect score (EMN) was derived from 138 mothers (n = 51 in the neglectful group; n = 87 in the control non-neglectful group) having young children. Differential methylation between groups was utilized to derive the EMNs adjusted for education level, age, experimental variables, and blood cell types in saliva samples.</p><p><strong>Results: </strong>Structural equation modeling: X² (29) = 37.81; p = 0.127; RMSEA = 0.048, confirmed that EMNs link their early experience of physical neglect to current reports of psychopathological symptoms, lower cognitive status, and observed poor mother-child emotional availability. A third of the genes annotated to the CpGs that affect EMNs are related to cognitive impairment and neurodegenerative and psychopathological disorders.</p><p><strong>Conclusions: </strong>EMNs are a novel index to assess the contribution of DNA methylations as a neglected girl to later neglectful caregiving behavior and other negative effects. The evidence provided expands the possibilities for earlier interventions on the neglect condition to prevent and ameliorate the direct or indirect epigenetic impact of maternal adversities on mother-child care, helping to break the cycle of maltreatment.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"46"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584201","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":"Epigenome-wide analysis reveals potential biomarkers for radiation-induced toxicity risk in prostate cancer.","authors":"Carlos Lopez-Pleguezuelos, Miguel E Aguado-Barrera, Ana Carballo-Castro, Paula Peleteiro, Patricia Calvo-Crespo, Begoña Taboada-Valladares, Ramón Lobato-Busto, Olivia Fuentes-Ríos, Javier Galego-Carro, Carla Coedo-Costa, Antonio Gómez-Caamaño, Ana Vega","doi":"10.1186/s13148-025-01846-8","DOIUrl":"10.1186/s13148-025-01846-8","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer is the second most common cancer globally, with radiation therapy (RT) being a key treatment for clinically localized and locally advanced cases. Given high survival rates, addressing long-term side effects of RT is crucial for preserving quality-of-life. Radiogenomics, the study of genetic variations affecting response to radiation, has primarily focussed on genomic biomarkers, while DNA methylation studies offer insights into RT responses. Although most research has centred on tumours, no epigenome-wide association studies have explored peripheral blood biomarkers of RT-induced toxicities in prostate cancer patients. Identifying such biomarkers could reveal molecular mechanisms underlying RT response and enable personalized treatment.</p><p><strong>Methods: </strong>We analysed 105 prostate cancer patients (52 cases and 53 controls). Cases developed grade ≥ 2 genitourinary and/or gastrointestinal late toxicity after 12 months of starting RT, whereas controls did not. An epigenome-wide association study of post-RT toxicities was performed using the Illumina MethylationEPIC BeadChip, adjusting for age and cell type composition. We constructed two methylation risk scores-one using differentially methylated positions (MRSsites) and another using differentially methylated regions (MRSregions)-as well as a Support Vector Machine-based methylation signature (SVMsites). We evaluated RT effects on biological age and stochastic epigenetic mutations within established radiation response pathways. Gene Ontology and pathway enrichment analyses were also performed.</p><p><strong>Results: </strong>Pre-RT methylation analysis identified 56 differentially methylated positions (adjusted p-value ≤ 0.05), and 6 differentially methylated regions (p-value ≤ 0.05) associated with the genes NTM, ACAP1, IL1RL2, VOOP1, AKR1E2, and an intergenic region on chromosome 13 related to Short/Long Interspersed Nuclear Elements. Both Methylation Risk Scores (MRSsites AUC = 0.87; MRSregions AUC = 0.89) and the 8-CpG Support Vector Machine signature (SVMsites AUC = 0.98) exhibited strong discriminatory accuracy in classifying patients in the discovery cohort. Gene ontology analysis revealed significant enrichment (adjusted p-value ≤ 0.05) of genes involved in DNA repair, inflammatory response, tissue repair, and oxidative stress response pathways.</p><p><strong>Conclusions: </strong>Epigenetic biomarkers show potential for predicting severe long-term adverse effects of RT in prostate cancer patients. The identified methylation patterns provide valuable insights into toxicity mechanisms and may aid personalized treatment strategies. However, validation in independent cohorts is essential to confirm their predictive value and clinical applicability.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"43"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572025","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":"First evidence of epigenetic modulation of human gene methylation by microalga Aphanizomenon flos-aquae (AFA) in inflammation-related pathways in intestinal cells.","authors":"Flores Naselli, Sara Volpes, Paola Sofia Cardinale, Sabrina Micheli, Adele Cicio, Gabriel Dylan Scoglio, Roberto Chiarelli, Maria Grazia Zizzo, Pasquale Picone, Fabio Caradonna, Domenico Nuzzo","doi":"10.1186/s13148-025-01849-5","DOIUrl":"10.1186/s13148-025-01849-5","url":null,"abstract":"<p><p>The microalga Aphanizomenon flos-aquae (AFA) has garnered attention for its potential therapeutic benefits in various health conditions, primarily through its use in nutraceutical formulations. While biological effects of AFA have been extensively studied in preclinical models, including murine systems, its nutrigenomic and epigenetic impacts remain underexplored. This study investigates the potential epigenetic mechanisms of AFA, focusing on its ability to modulate DNA methylation, a key regulatory process in gene expression. Specifically, we examined the influence of AFA on the methylation status of genes encoding pro-inflammatory interleukins, as these cytokines play a crucial role in immune response modulation and inflammation. Given the known impact of AFA on inflammatory markers, we aimed to determine whether the effects of AFA involve direct or indirect modulation of DNA methylation patterns in genes associated with inflammation. Our findings, presented here for the first time, reveal the capacity of AFA to influence DNA methylation, with implications for its role in cellular regulatory processes. These results warrant further investigation into precise mechanisms of action of AFA and its potential in clinical applications targeting inflammation-related pathways.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"44"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572035","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":"Protein epigenetic scores and overall mortality in the longitudinal Swedish Adoption/Twin Study of Aging (SATSA).","authors":"Thaís Lopes De Oliveira, Arianna March, Jonathan K L Mak, Nancy L Pedersen, Sara Hägg","doi":"10.1186/s13148-025-01843-x","DOIUrl":"10.1186/s13148-025-01843-x","url":null,"abstract":"<p><strong>Introduction: </strong>DNA methylation (DNAm) has a functional role in gene regulation, and it has been used to estimate various human characteristics. Variation in DNAm is associated with aging and variability of the proteome. Therefore, understanding the relationship between blood circulating proteins, aging, and mortality is critical to identify disease-causing pathways. We aimed to estimate the association between protein epigenetic scores (EpiScores) and overall mortality in the Swedish Adoption/Twin Study of Aging (SATSA).</p><p><strong>Methods: </strong>We included information from 374 individuals collected between 1992 and 2014. Our exposures were 109 protein EpiScores generated using DNAm data and prediction models by the MethylDetectR shiny app. All-cause mortality was the outcome of interest. To estimate the protein EpiScores associations with all-cause mortality, we fitted Cox proportional hazard models adjusted for age, sex, education, smoking status, body mass index, and occupation. We also conducted co-twin control analyses to control for shared familial factors.</p><p><strong>Results: </strong>The mean age of participants at the first assessment was 68.6 years. In total, nine protein EpiScores (e.g., Stanniocalcin 1) were associated with a higher risk for all-cause mortality. In contrast, five protein EpiScores (e.g., Prolyl endopeptidase) were associated with a lower risk for all-cause mortality.</p><p><strong>Conclusion: </strong>The protein EpiScores associated with an increased mortality risk represent proteins involved in metabolic functions, immune response, and inflammation. Conversely, those associated with a lower risk represent proteins involved in neurogenesis and cellular functions. Overall, it is possible to predict protein levels from DNAm data that could have clinical relevance.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"41"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566225","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":"Mendelian randomization provides a multi-omics perspective on the regulation of genes involved in ribosome biogenesis in relation to cardiac structure and function.","authors":"Shuxu Wei, Ronghuai Shen, Xiaojia Lu, Xinyi Li, Lingbin He, Youti Zhang, Jiahang Yang, Zhouwu Shu, Xianxi Huang","doi":"10.1186/s13148-025-01850-y","DOIUrl":"10.1186/s13148-025-01850-y","url":null,"abstract":"<p><strong>Background: </strong>Ribosome biogenesis (RiboSis) is a complex process for generating ribosomes, the cellular machinery responsible for protein synthesis. Dysfunctional RiboSis can disrupt cardiac structure and function, contributing to cardiovascular diseases. This study employed a Mendelian randomization (MR) approach, integrating multi-omics data, to investigate the relationship between RiboSis-related genes and standard cardiac structure and function.</p><p><strong>Methods: </strong>We utilized summary stats for methylation, RNA splicing, and gene expression, and UK Biobank cardiopulm MRI genetic associations (N = 41,135). MR evaluated RiboSis gene features against traits, complemented by hypothesis prioritization for multi-trait colocalization (HyPrColoc) and colocalization. Composite scores ranked RiboSis genes, and phenome-wide association study (PheWAS) with scQTLbase instrumental variables (IVs) confirmed results.</p><p><strong>Results: </strong>We identified 15 RiboSis-related genes: HEATR1, SENP3, ERI1, ERCC2, TSR1, UTP11, DDX17, SMARCB1, NIP7, ERAL1, NOP56, RPL10A, EIF6, EXOSC9, and NOP58. Notably, HEATR1 and SENP3 were ranked in the top quartile (Q1), scoring 25. In validation cohort, 12 genes associated with cardiac structures, functions, diseases. Only ERAL1, TSR1, and NIP7 lacked significant associations with cardiac traits.</p><p><strong>Conclusion: </strong>Our multi-omics MR analysis identified 15 RiboSis-related genes associated with cardiac risk, with 12 further validated through gene set enrichment analysis. These findings suggest a link between RiboSis and cardiac health, enhancing understanding of cardiac disease mechanisms.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"42"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566224","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":"Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices.","authors":"Zequn Zheng, Yongfei Song, Xinhan Li, Tao Luo, Xuerui Tan","doi":"10.1186/s13148-025-01851-x","DOIUrl":"10.1186/s13148-025-01851-x","url":null,"abstract":"<p><strong>Background: </strong>Tobacco and alcohol are recognized risk factors for heart disease, yet their causal effects on electrocardiogram (ECG) signaling and mechanisms remain unclear. Previous studies may be susceptible to confounding or bias, and this study dissected the genetic architecture linking tobacco and alcohol consumption with P-wave duration, PR interval, and QT interval.</p><p><strong>Methods: </strong>Utilizing genetic instruments for tobacco and alcohol consumption, associated methylation quantitative trait locus (mQTL), and summary-level GWAS data for ECG indices, we assessed heritability and genetic causal associations using linkage disequilibrium score regression and Mendelian randomization (MR) analysis. Fine mapping was performed via colocalization analysis and summary-data-based MR (SMR) to identify potential shared genetic variants.</p><p><strong>Results: </strong>A positive causal relationship was found between drinks per week (DrnkWk) and QT interval [β (95%CI): 1.06 (0.91, 5.05), P = 0.005], with causality substantiated through multiple robust MR models. Multivariable MR confirmed independence from smoking phenotypes. In epigenetic MR analyses, two alcohol-related CpG loci (cg03345232 and cg04605617) were causally associated with QT interval changes, with cg04605617 mapping to PLA2G2C gene significantly prolonging QT. The mQTL rs10916683 at cg04605617 is a strong eQTL for PLA2G2C. Additionally, cg03345232 shared a causal variant (rs12881206) with QT interval predisposition through colocalization analysis. SMR analysis did not identify shared putative functional genes passing the HEIDI test between DrnkWk and the QT interval.</p><p><strong>Conclusions: </strong>There is a causal relationship between DrnkWk and QT interval prolongation, and targeting specific DNA methylation sites like cg04605617 mapped to PLA2G2C may provide novel targets for preventing QT interval prolongation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"40"},"PeriodicalIF":4.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556013","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":"Advances in epigenetic treatment of adult T-cell leukemia/lymphoma: a comprehensive review.","authors":"Arash Letafati, Rabeeh Mehdigholian Chaijani, Fahime Edalat, Nazila Eslami, Hanieh Askari, Farideh Askari, Sara Shirvani, Hamed Talebzadeh, Mahdiyeh Tarahomi, Nila MirKhani, Faeze Karimi, Mehdi Norouzi, Sayed-Hamidreza Mozhgani","doi":"10.1186/s13148-025-01841-z","DOIUrl":"10.1186/s13148-025-01841-z","url":null,"abstract":"<p><p>Human T-cell lymphotropic virus type 1 (HTLV-1) infection causes the uncommon and deadly cancer known as adult T-cell leukemia/lymphoma (ATLL), which affects mature T cells. Its clinical appearance is varied, and its prognosis is often miserable. Drug resistance to conventional therapies confers significant therapeutic challenges in the management of ATLL. This review discusses the emerging role of epigenetic medical advances in the treatment of ATLL, focusing on DNA methyltransferase inhibitors, histone deacetylase inhibitors, histone methyltransferase inhibitors, and BET inhibitors. Indeed, several classes of epigenetic therapies currently exhibit trailed efficacy in preclinical and clinical studies: DNA methyltransferase inhibitors like azacitidine and decitabine reexpression of silenced tumor suppressors; histone deacetylase inhibitors like vorinostat and romidepsin induce cell cycle arrest and apoptosis; bromodomain and extra-terminal inhibitors like JQ1 disrupt oncogenic signaling pathways. Whereas preclinical and early clinical data indicate modest to good efficacy for such treatments, significant challenges remain. Here, we discuss the current state of understanding of epigenetic dysregulation in ATLL and appraise the evidence supporting the use of these epi-drugs. However, despite the opened doors of epigenetic treatment, much more research is required with regard to showing the best combinations of drugs and their resistance mechanisms, the minimization of adverse effects, and how this hope will eventually be translated into benefit for the patient with ATLL.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"39"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536761","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}