Clinical Epigenetics最新文献

{"title":"Direct analysis of transcription factor protected cfDNA in plasma by ChIP-seq: measurement of altered CTCF binding in cancer is a novel biomarker for liquid biopsy.","authors":"Dorian Pamart, Brieuc Cuvelier, Adrien Govaerts, Muriel Chapelier, Marielle Herzog, Andrew Retter, Thomas Bygott, Jean-Valery Turatsinze, Benjamin P Berman, Jacob Micallef","doi":"10.1186/s13148-026-02205-x","DOIUrl":"https://doi.org/10.1186/s13148-026-02205-x","url":null,"abstract":"<p><strong>Background: </strong>The aggregate presence of cell free CTCF-DNA (cfCTCF-DNA) nucleoproteins in plasma has been reported. But the occupancy of individual CTCF binding sites in plasma cfCTCF-DNA has not been studied.</p><p><strong>Results: </strong>For the first time, we have isolated endogenous plasma cfCTCF-DNA by chromatin immunoprecipitation (ChIP) and sequenced the associated cfDNA (ChIP-Seq) in samples from cancer patients and healthy subjects. The mean observed enrichment of plasma cfCTCF-DNA by ChIP was 180-fold with a mean CTCF recovery of 48%. Background cfDNA, primarily in the form of nucleosomes, was almost completely physically removed (> 99.7%) by ChIP and the remainder was removed bioinformatically. cfCTCF-DNA sequences were partitioned into low or high affinity binding cfCTCF-DNA nucleoproteins in silico, on the basis of binding motif concordance with the consensus CTCF binding motif. We observed that cfCTCF-DNA was quantitatively and qualitatively different in samples from healthy subjects or cancer patients. High affinity cfCTCF-DNA nucleoproteins were present only in the plasma of cancer patients and not in samples from healthy subjects. Testing of small developmental and validation sample cohorts for ChIP-seq peaks for a 14 member panel of high affinity CTCF loci sequences, showed excellent specificity and sensitivity for cancer detection.</p><p><strong>Conclusions: </strong>Plasma sequence data sets comprising > 99% pure CTCF protected ctDNA can be prepared using a 2-step process involving the physical removal of most background cfDNA in vitro, followed by removal of all remaining background cfDNA in silico. CTCF plasma ChIP-seq represents a novel liquid biopsy method for a novel class of liquid biopsy biomarkers.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548075","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":"Inflammation mediates the Pace of aging based on DNA methylation on mortality from NHANES 1999-2002: a national prospective cohort study.","authors":"Jihua Feng, Yuting Liang, Jie Zhou, Yongbing Yu, Xiaowen Zheng, Jingjia Mo, Zhiqing Huang, Jianfeng Zhang","doi":"10.1186/s13148-026-02206-w","DOIUrl":"https://doi.org/10.1186/s13148-026-02206-w","url":null,"abstract":"<p><strong>Background: </strong>Global population aging underscores the urgent need for biomarkers quantifying biological aging trajectories. While DNA methylation-derived pace of aging (DunedinPoAm) measures individual differences, its generalizability across diverse populations and mechanistic links to systemic inflammation remain underexplored. This study aimed to systematically examine the longitudinal associations between the DunedinPoAm and all‑cause mortality in a multiethnic cohort, and to quantify the extent to which systemic inflammatory biomarkers mediate these associations using causal mediation analysis.</p><p><strong>Methods: </strong>For this cohort study, information on a nationally representative cohort of 21,004 U.S. adults was extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2002, along with the NHANES Linked Mortality File, which ascertained mortality through December 31, 2019. The exposures were Pace of aging (DunedinPoAm) and inflammation. The survival outcome measured was all-cause mortality. We employed Cox proportional hazards models, Kaplan-Meier survival curves, restricted cubic splines, and Bayesian mediation frameworks to evaluate mortality risk, explore non-linear dose-response relationships, and investigate inflammatory mediation.</p><p><strong>Results: </strong>Data were analyzed from 2,532 participants, with a mean follow-up duration of 18.5 ± 1.29 years. Higher DunedinPoAm quartiles exhibited graded mortality risks (Q4 vs. Q1: HR = 2.50, 95% CI 1.84-3.38), which persisted after multivariable adjustment. Restricted cubic splines revealed a non-linear association (P for overall < 0.001; P for nonlinearity < 0.001), indicating the presence of threshold effects. Systemic inflammation mediated 2.33-23.5% of the mortality risk associated with DunedinPoAm, driven by CD4 + T cells, B cells, CRP and comprehensive inflammatory indices. A significant interaction with diabetes (P for interaction = 0.026) underscored metabolic dysregulation as a vulnerability factor.</p><p><strong>Conclusion: </strong>DunedinPoAm predicts all-cause mortality in a non-linearly manner across multiethnic populations, partially mediated by pathways associated with inflammaging. The observed diabetes-specific interactions and threshold effects indicate the potential for precision approaches targeting high-risk subgroups. These findings support the integration of DunedinPoAm into gerotherapeutic trials and public health strategies aimed at addressing disparities in aging.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469357","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":"Biological age acceleration and bradyarrhythmia: evidence from clinical and epigenetic perspectives.","authors":"Zheng-Qi Song, Lu-Jie Huang, Ke Liu, Sheng-Ke Wu, Jia-Rui Chen, Yan-Zhen Pei, Yi-He Chen","doi":"10.1186/s13148-026-02188-9","DOIUrl":"https://doi.org/10.1186/s13148-026-02188-9","url":null,"abstract":"<p><strong>Background: </strong>To date, effective preventive and therapeutic strategies for early-stage bradyarrhythmia remain limited.</p><p><strong>Methods: </strong>We first calculated two well-established biological aging (BA) measures (Klemera-Doubal Method [KDM] and Phenotypic Age [PhenoAge]), with BA acceleration defined as the residual from regressing each BA measure on chronological age. Cox proportional hazards models were used to evaluate the effects of BA acceleration on bradyarrhythmia risk. We then conducted epigenetic Mendelian randomization (MR) and colocalization analyses to prioritize aging-related DNA methylation CpG sites for bradyarrhythmias.</p><p><strong>Results: </strong>In the UK Biobank cohort of 298,214 individuals, per 1-SD increase in PhenoAge acceleration and KDM-BA acceleration were significantly associated with a 13% (HR = 1.13, 95% CI 1.11-1.15, P < 0.001) and 11% (HR = 1.11, 95% CI 1.09-1.13, P < 0.001) higher incidence of bradyarrhythmia. Epigenetic MR and colocalization analyses suggested that cg11410859 (SCN5A), cg18249173 (TBX20), cg07185587 (AKAP6), cg16555537 (TRIP6), cg10459018, cg03473532 (MKLN1), and cg13654588 (PRLHR) were associated with a reduced risk of bradyarrhythmias, whereas cg25286333 (RNF207) and cg02447380 (RAB42) were associated with an increased risk of bradyarrhythmias.</p><p><strong>Conclusions: </strong>In summary, our study elucidated the role of accelerated biological aging and underlying epigenetic modifications in bradyarrhythmia, providing novel insights into its prevention and treatment.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469345","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":"Aging-driven transcriptional programs in diabetic kidney disease: multi-omics discovery of diagnostic biomarkers and drug-repurposing targets.","authors":"Xue Hu, Yingzhuo Li, Yang Wang, Bosheng Luo, Chunjuan Xia, Jiaping Wang","doi":"10.1186/s13148-026-02207-9","DOIUrl":"https://doi.org/10.1186/s13148-026-02207-9","url":null,"abstract":"<p><strong>Background: </strong>Diabetic kidney disease (DKD) is the primary global cause of end-stage renal disease. However, the aging-related gene networks driving its progression remain unclear.</p><p><strong>Methods: </strong>In this study, we integrated bioinformatics and experiments to screen for age-related hub genes in DKD and explore their diagnostic and therapeutic values. Transcriptomic datasets and aging-related gene databases were combined to obtain candidate differentially expressed genes enriched in the PI3K-Akt and JAK-STAT pathways. LASSO and Random Forest algorithms were applied to screen core hub genes, and a logistic diagnostic model was constructed for verification. Single-cell sequencing was utilized to clarify the main cell populations expressing key genes. Molecular docking and dynamics simulations were performed to analyze the binding stability of candidate drugs and target genes. High-glucose cell models and DKD rat models were established, and RT-qPCR, western blot, and pathological staining assays were used to validate the expression changes of key genes and the regulatory effects of drugs.</p><p><strong>Results: </strong>Nine hub genes (CLU, EGF, SLC16A7, MYC, RPA1, RB1, APOC3, SYK, and NR3C1) were finally screened out. The constructed logistic diagnostic model achieved an AUC of 0.881 in external verification. Glomerular endothelial cells and mesangial cells were identified as the main cell populations expressing these hub genes. Molecular simulation results confirmed the stable binding of fostamatinib to SYK and selexipag to APOC3. In vivo and in vitro validation experiments demonstrated that the two candidate agents could suppress NF-κB pathway activation, inflammatory cytokine release, and cellular senescence.</p><p><strong>Conclusion: </strong>In this study, we identified age-related hub genes, constructed a reliable diagnostic signature, and suggested SYK-fostamatinib and APOC3-selexipag as potential drug-repurposing candidates for DKD, which requires further experimental and clinical validation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469364","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":"Epigenome-wide association study meta-analysis of wellbeing.","authors":"Meike Bartels, Margot P van de Weijer, Natalia Azcona-Granada, Bart M L Baselmans, Matthew Suderman, Mette Soerensen, Jadwiga Buchwald, Rosa H Mulder, Rajesh Rawal, Michelle Luciano, Marc Jan Bonder, Priyanka Choudhary, Estelle Lowry, Penelope A Lind, Joel Schwartz, Birgit Debrabant, Miina Ollikainen, Janine F Felix, Marian J Bakermans-Kranenburg, Henning Tiemeier, Christian Gieger, Melanie Waldenberger, Nicholas G Martin, Pantel Vokonas, Andrea A Baccarelli, Kaare Christensen, Jaakko Kaprio, Marinus H van IJzendoorn, Rebecca T Emeny, Ian J Deary, Lude Franke, Sylvain Sebert, Allan F McRae, Avron Spiro, Jenny van Dongen","doi":"10.1186/s13148-026-02202-0","DOIUrl":"https://doi.org/10.1186/s13148-026-02202-0","url":null,"abstract":"<p><p>Wellbeing is associated with both behavioral phenotypes as well as several key life outcomes, such as health, employment, and coping with stressful events. These phenotypes associated with wellbeing could be potential indicators of differential epigenetic patterns between individuals that differ in their levels of wellbeing. We performed the largest epigenome-wide (EWAS) meta-analysis of wellbeing to date by combining whole blood DNA methylation data (Illumina 450K array) from 13 cohorts from Europe, Australia, and the USA (N = 10,757 participants). After correcting for smoking and BMI, no epigenome-wide significant methylation sites were identified. We tested whether a weighted methylation score (MS) based on leave-one-cohort-out EWAS meta-analysis summary statistics predicted wellbeing in an independent cohort, and whether prediction was significant over and above the polygenic score (PGS) for wellbeing. The MS was associated with wellbeing (variance explained = 0.22%, p = 0.03) and was no longer significant after adding the polygenic score (PGS; variance explained = 0.43%, p = 0.0046, MS; variance explained = 0.07%, p = 0.2842). We further compared DNA methylation levels in 16 pairs of monozygotic twins discordant for wellbeing. These analyses revealed no significant within-pair DNA methylation differences at the top-sites from the meta-analysis or in MS. Our results suggest that larger EWAS meta-analyses with uniform phenotype assessment are required to identify methylation sites associated with wellbeing.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444781","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":"The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.","authors":"Zhuo Zhang, Qiaoling Peng, Shaohu Wang, Quan Xun, Xingming Chen, Mingliang Zhou, Jianguan Luo, Lishun Yang, Chunming Tang, Yiqing Luo, Junlin Liu","doi":"10.1186/s13148-026-02200-2","DOIUrl":"https://doi.org/10.1186/s13148-026-02200-2","url":null,"abstract":"<p><strong>Background: </strong>Despite the dominance of M2-polarized tumor-associated macrophages in colorectal cancer (CRC), the metabolic-epigenetic mechanisms by which CRC cells sustain this immunosuppressive phenotype remain elusive. We hypothesize that a glycolysis-driven positive feedback loop, involving PKM2-mediated lactate production and subsequent H4K12 lactylation (H4K12la) at the PKM2 promoter, enables CRC cells to metabolically reprogram macrophages toward M2 polarization. This study aims to characterize this regulatory circuit and determine its potential as a therapeutic target to enhance immunotherapy efficacy.</p><p><strong>Methods: </strong>We used qRT-PCR, Western blot, and metabolic flux analysis (ECAR, lactate production, 2-NBDG uptake) to assess the glycolysis-H4K12la-PKM2 axis in CRC cells following genetic manipulation (PKM2 overexpression/knockdown) and pharmacological inhibition (2-DG). Chromatin immunoprecipitation (ChIP-qPCR) quantified H4K12la enrichment at the PKM2 promoter. The functional impact on macrophage polarization was evaluated using THP-1-derived and primary human macrophage co-culture systems (flow cytometry for CD163), complemented by an in vivo xenograft model.</p><p><strong>Results: </strong>PKM2 was highly expressed in CRC cells and sustained aerobic glycolysis, leading to elevated intracellular lactate and H4K12la levels. Mechanistically, H4K12la accumulated at the PKM2 promoter, forming a positive feedback loop that amplified glycolytic flux. Disruption of this loop-via PKM2 knockdown or glycolytic inhibition-suppressed M2 macrophage polarization in vitro. In vivo, combined PKM2 knockdown and 2-DG treatment synergistically inhibited tumor growth, reduced M2 macrophage infiltration, and diminished H4K12la levels.</p><p><strong>Conclusion: </strong>Our findings identify a glycolysis-H4K12la-PKM2 positive feedback loop in CRC cells that drives M2 macrophage polarization. Interrupting this circuit offers a promising strategy to reconfigure the tumor immune landscape and improve immunotherapeutic outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435457","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":"Preliminary study on PAX1/JAM3 methylation and HPV viral load in CIN3-like squamous cell carcinoma: Are there differences from CIN3 and early invasive carcinoma?","authors":"Mingzhu Li, Xiaobo Zhang, Xing Zhao, Jixian Wang, Chao Zhao, Yun Zhao, Jingran Li, Danhua Shen, Lihui Wei","doi":"10.1186/s13148-026-02201-1","DOIUrl":"https://doi.org/10.1186/s13148-026-02201-1","url":null,"abstract":"<p><strong>Objective: </strong>Cervical intraepithelial neoplasia grade 3 (CIN 3)-like squamous cell carcinoma (SCC) is a recently identified subtype of cervical cancer with a deceptive growth pattern. It mimics the phenotype of CIN 3, involving endocervical crypts, presenting significant challenges and potential for diagnostic confusion. This study aims to clarify the differences in epigenetic profiles and HPV viral load(VL) among CIN 3, CIN 3-like SCC, early invasive SCC, and invasive SCC.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 138 cases of cervical high-grade lesions and SCC diagnosed at Peking University People's Hospital from March 2022 to June 2024. The cases included 65 high-grade squamous intraepithelial lesions (HSIL) [23 CIN 2 and 42 CIN 3] and 73 SCC [27 CIN 3-like SCC, 21 early invasive SCC, and 25 invasive SCC]. Histological samples were analyzed for methylation levels of the epigenetic factors PAX1 and JAM3, as well as HPV VL.</p><p><strong>Results: </strong>Methylation levels of PAX1 and JAM3, as well as total HPV VL, were significantly higher in cervical cancer than in HSIL(< 0.001). The PAX1 methylation level of CIN3 was significantly lower than that of invasive SCC, but there was no significant difference compared with CIN3 and CIN 3-like SCC; For the PAX1/JAM3 methylation levels in CIN 3-like SCC, no statistically significant differences were observed when compared with those in early invasive SCC and invasive SCC. The HPV VL in CIN 3-like SCC was significantly higher than that in CIN 3 and early invasive SCC, but no significant difference was found compared with invasive SCC. In the same stage of FIGO, although PAX1/JAM3 methylation and HPV VL (especially HPV16/18 VL) showed a tendency to increase in CIN3-like SCC compared with early invasive SCC, the difference was not significant, further expansion of sample size is needed to confirm this.</p><p><strong>Conclusion: </strong>PAX1 and JAM3 methylation levels are significantly higher in SCC than HSIL, but no difference in methylation levels was observed between CIN 3-like SCC, early invasive SCC, and invasive SCC. Total HPV VL (especially HPV16/18 VL) in CIN3-like SCC is significantly higher than that in CIN3 and early invasive SCC, suggesting potential shared and distinct features in epigenetics and HPV VL between CIN3-like SCC and early invasive SCC, which need more molecular biology research to explore the difference.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419298","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":"Correction: GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.","authors":"Janina Müller, Emre Sofyali, Luisa Schwarzmüller, Yael Aylon, Eviatar Weizman, Lisa Schlicker, Katherine Kelly, Simone Borgoni, Simin Oz, Cole Stocker, Sara Burmester, Angelika Wörner, Sabine Karolus, Birgitta E Michels, Daniela Heiss, Rainer Will, Veronica Rodrigues de Melo Costa, Pavlo Lutsik, Dieter Weichenhan, Ilse Hofmann, Nishanth Belugali Nataraj, Yosef Yarden, Luca Magnani, Christoph Plass, Almut Schulze, Cindy Körner, Moshe Oren, Stefan Wiemann","doi":"10.1186/s13148-026-02203-z","DOIUrl":"10.1186/s13148-026-02203-z","url":null,"abstract":"","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419256","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 editing approaches maturity: AI-driven precision design, delivery innovation, and the road to clinical translation.","authors":"Shiqi Chang, Di Lu, Yuyuan Jin, Yilei He, Yue Zhao, Xinyu Xie, Jingjing Guo, Wenbing Xie, Yong Tao","doi":"10.1186/s13148-026-02194-x","DOIUrl":"https://doi.org/10.1186/s13148-026-02194-x","url":null,"abstract":"<p><p>Epigenetic editing achieves durable gene silencing through targeted modification of chromatin and DNA methylation states without altering the genomic sequence-modifications that remain fundamentally reversible compared with genome editing. Long constrained by transient efficacy, insufficient precision, and delivery bottlenecks, the field reached a critical inflection point in 2024-2025, measurable through three quantifiable criteria: (1) mechanistic durability-silencing maintained across ≥ 450 cell divisions in vitro and ≥ 12 months in vivo without continued editor expression; (2) delivery competence-tissue-selective transduction at > 50% efficiency in liver, muscle, and whole brain via engineered lipid nanoparticle and AAV platforms; and (3) clinical validation-advancement of multiple first-in-human trials. The inaugural trial in epigenetic editing was OTX-2002 (targeting MYC-driven malignancies, MYCHELANGELO study), initiated in October 2022, followed by TUNE-401 for chronic hepatitis B (Phase Ib, November 2024) and EPI-321 for facioscapulohumeral muscular dystrophy (Phase I/II, first patient dosed August 2025). Artificial intelligence contributes at distinct levels: deep learning platforms have directly accelerated clinical-stage LNP formulation screening and AAV capsid prediction; AlphaFold3 has optimized protein-DNA interaction validation without yet entering clinical programs; and the 2025 de novo design of DNA-binding proteins smaller than 65 amino acids represents a proof-of-concept breakthrough with zero clinical precedent. This review comprehensively analyzes epigenetic editing's technological maturation, provides a tiered assessment of AI's realized and anticipated contributions, critically evaluates the emerging clinical landscape, and identifies decisive unresolved challenges-including long-term stability in non-dividing cells, the lack of monitoring systems and intervention protocols needed to implement reversibility in clinical practice, and manufacturing access barriers. We argue that epigenetic editing is progressively establishing itself as a distinctive therapeutic modality characterized by durable efficacy and sequence-independent safety-reversibility as a theoretical safety mechanism has been validated preclinically, but the monitoring and intervention infrastructure required for its clinical implementation remains to be established. Long-term human validation remains the outstanding core question.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410834","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":"Tumor-type specific methylation patterns of MTAP in human samples and cell lines.","authors":"Luis Álvarez-Carrión, Dalma Müller, Manuel Pedregal, Lucia Paniagua, Irene Gutiérrez Rojas, Verónica Alonso, Jorge Bartolomé, Marta Amann, Esther Cabañas Morafraile, Bernard Doger, Emiliano Calvo, Juan Antonio Ardura, Balázs Győrffy, Víctor Moreno, Alberto Ocana","doi":"10.1186/s13148-026-02199-6","DOIUrl":"https://doi.org/10.1186/s13148-026-02199-6","url":null,"abstract":"<p><p>Loss of methylthioadenosine phosphorylase creates a therapeutically dependency on PRMT5, yet current strategies select patients based only on MTAP genomic deletion. We performed an integrated analysis of DNA methylation and gene expression using TCGA, TARGET and ENCODE data to identify alternative mechanisms of MTAP inactivation. A promoter-proximal CpG site (cg25162921) showed a frequent hypermethylation and strong inverse correlation with MTAP mRNA expression across multiple tumor types and cell lines, including lung squamous cell carcinoma and glioblastoma. These findings identify promoter hypermethylation as a copy-number-independent mechanism of MTAP silencing and support epigenetic profiling evaluation in tumor samples into MTAP-based precision oncology.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410893","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}