Clinical Epigenetics最新文献

{"title":"High prevalence of constitutional BRCA1 epimutation in patients with early-onset triple-negative breast cancer.","authors":"Mathias Schwartz, Sabrina Ibadioune, Hélène Delhomelle, Solenn Barraud, Sandrine M Caputo, Olfa Trabelsi-Grati, Marie-Charlotte Villy, Anthony Laugé, Roseline Tang, Etienne Rouleau, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Éric Pasmant, Lisa Golmard, Chrystelle Colas, Ivan Bièche","doi":"10.1186/s13148-025-01885-1","DOIUrl":"10.1186/s13148-025-01885-1","url":null,"abstract":"<p><p>Between 5 and 8% of the general population carry a constitutional methylation of the BRCA1 promoter (\"epimutation\"). Several studies have suggested that these BRCA1 epimutations confer an increased risk of breast cancer, in particular triple-negative breast cancer (TNBC), with an earlier onset than in the general population. However, those studies relied on very few patients with early-onset TNBC. Using specific Methylation-Sensitive High-Resolution Melting, we assessed BRCA1 epimutation prevalence in a large cohort of 112 early-onset (≤ 30 years-old) TNBC patients with no genetic cancer-predisposing pathogenic variants (PVs). We compared this cohort to 87 early-onset TNBC patients carrying cancer-predisposing PVs and to 93 late-onset (≥ 70 years-old) TNBC with no cancer-predisposing PVs. We observed a high prevalence of BRCA1 epimutation in blood cells from early-onset TNBC patients with no cancer-predisposing PVs (38/112, 33.9% [95% confidence interval: 25.4-43.6%]) as compared to early-onset patients with cancer-predisposing PVs (1/87, 1.1% [0.1-7.1%], p value < 0.001) and late-onset patients (11/93, 11.8% [6.3-20.6%], p value < 0.001). These differences remained significant when restricting to epimutations with low variant epiallele frequencies (VEF under 1%). Our results highlight the role of constitutional BRCA1 epimutations in early-onset TNBC risk and call for their integration into multifactorial models used to compute personalized breast cancer risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"91"},"PeriodicalIF":4.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215058","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 loss of mouse Nlrp2 alters the transcriptome and DNA methylome in GV oocytes and impairs zygotic genome activation in embryos.","authors":"Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van den Veyver","doi":"10.1186/s13148-025-01889-x","DOIUrl":"10.1186/s13148-025-01889-x","url":null,"abstract":"<p><strong>Background: </strong>NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.</p><p><strong>Results: </strong>We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the transcriptome of GV oocytes and 2-cell embryos from WT and Nlrp2-null females. The absence or reduction of NLRP2 did not alter the distinctive global DNA methylation landscape of GV oocytes, including their unique bimodal methylome patterns and methylation at the germline differentially methylated regions (gDMRs) of imprinted genes. However, altered methylation was observed in a small subset of oocyte-characteristic hyper- and hypomethylated domains and within a minor fraction of genomic regions, particularly in Nlrp2-null oocytes. Transcriptome profiling revealed substantial differences between the Nlrp2-null and WT GV oocytes, including deregulation of many crucial factors involved in oocyte transcriptome modulation and epigenetic reprogramming. Moreover, maternal absence of NLRP2 significantly altered the transcriptome of heterozygous embryos from Nlrp2-null females compared to WT embryos, whereas the transcriptome of heterozygous embryos from Nlrp2-null males was not significantly different from that of WT embryos. Maternal absence of NLRP2 also negatively impacted MZT, as evidenced by the deregulation of a large subset of zygotic genome activation (ZGA)-related genes.</p><p><strong>Conclusions: </strong>This study demonstrates that NLRP2 is essential for shaping the transcriptome of GV oocytes and preimplantation embryos. Maternal loss of Nlrp2 negatively impacts ZGA. Our findings that the DNA methylome of Het and Nlrp2-null oocytes was subtly changed, and that gene-body DNA methylation differences did not correlate with gene expression differences, suggest that posttranscriptional changes in transcript stability, rather than altered transcription itself, are primarily responsible for the changed transcriptome of Nlrp2-null oocytes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"92"},"PeriodicalIF":4.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215059","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":"Impact of DNA methylation on the recurrence risk of stage I non-small cell lung cancer with EGFR mutations.","authors":"Yunyi Li, Zhihui Yang, Fang Wu, Qingchun Liang, James G Herman, Malcolm V Brock, Wenliang Liu, Fenglei Yu, Xue He, Chen Chen","doi":"10.1186/s13148-025-01899-9","DOIUrl":"10.1186/s13148-025-01899-9","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have demonstrated that patients with stage IB-IIIA non-small cell lung cancer (NSCLC) harboring EGFR mutations (EGFRm) can significantly benefit from adjuvant therapy with EGFR-TKIs. Nevertheless, there remains controversial in clinical practice about the use of EGFR-TKI adjuvant therapy for patients with stage IB EGFRm NSCLC.</p><p><strong>Methods: </strong>This retrospective cohort study was conducted at the Second Xiangya Hospital of Central South University. From January 2011 to December 2020, completely resected stage IA-IB NSCLC (8th TNM staging) patients with sensitive EGFR mutation were included. FFPE tumor and lymph node specimens were collected and subjected to the 8-gene methylation panel using modified MOB-qMSP approach. We employed stepwise regression to select variables and logistic regression to establish the predictive model. Cross-validation and decision curve analysis were performed.</p><p><strong>Results: </strong>A total of 242 patients with IA2-IB EGFRm NSCLC were included in the study. Among these patients, 86 constituted the recurrence (Rec) group, while 156 formed the non-recurrence (Non-Rec) group. Through stepwise logistic regression, seven crucial feature variables were identified, including five-gene methylation variables (CDO1, TAC1, p16, CDH13, and APC) and two clinical variables (tumor invasion and differentiation). The ROC analysis revealed an AUC of 0.873 for the model with these seven variables. Internal cross-validation demonstrated a model accuracy exceeding 77%. The nomogram and decision curve analysis underscored the clinical utility of the model. We calculated the total score for each patient based on the nomogram and divided the patients into high-risk and low-risk groups. The cumulative risk curves for both groups evidenced that the recurrence risk in the high-risk group was significantly higher than in the low-risk group. We further divided the dataset into two cohorts-stage IA2-IA3 patients and stage IB patients. The model maintained a high AUC value (0.879) in stage IA2-A3 patients.</p><p><strong>Conclusions: </strong>Our study demonstrates that the methylation of five genes-CDO1, TAC1, p16, CDH13, and APC-in N2 lymph nodes represents a strong biomarker panel for predicting recurrence in stage IB EGFRm NSCLC after curative resection. This approach also shows exceptional predictive accuracy for postoperative recurrence in stage IA2-IA3 EGFRm NSCLC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"90"},"PeriodicalIF":4.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207842","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 mediates the association between low-grade systemic inflammation and cardiovascular diseases: insight from the NHANES 1999-2002.","authors":"Xiaolang Chen, Jin Zhong, Yingnan Lv, Lancheng Wei, Huijiao Zhou, Yongmei Yang, Jinfan Chi, Zhen Lee, Huabei Wu, Haiying Zhang","doi":"10.1186/s13148-025-01895-z","DOIUrl":"10.1186/s13148-025-01895-z","url":null,"abstract":"<p><strong>Background: </strong>Currently, with the global aging of the population, inflammation, recognized as a hallmark in age-related diseases, has been studied and linked to cardiovascular diseases (CVD). However, limited evidence on whether inflammation modifies epigenetic aging and affects CVD risk.</p><p><strong>Methods: </strong>This study included 404 CVD patients and 1941 non-CVD individuals from the 1999-2002 National Health and Nutrition Examination Survey cross-sectional data. Low-grade systemic inflammation was assessed using C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and systemic inflammation response index (SIRI). Epigenetic age accelerations (EAAs) were calculated as the residuals between chronological and epigenetic ages: Horvath age acceleration (AgeAccel), AgeAccelHannum, and AgeAccelPheno. Weighted linear and logistic regression analyzed the associations between exposures and outcomes, with mediating effects assessed using the Sobel test.</p><p><strong>Results: </strong>After adjusting confoundings, the log-transformed NLR and SIRI were positively associated with CVD risk, and the odds ratio (OR) ranges from 1.260 to 1.354 (all P < 0.05). Furthermore, the ln-transformed CRP was positively associated with AgeAccelHannum and AgeAccelPheno, and the coefficient (β) ranges from 0.505 to 1.304 (all P < 0.05); the ln-transformed NLR and SIRI were positively associated with all three EAAs, and the β ranges from 0.392 to 2.212 (all P < 0.005). Additionally, 1-unit increase in AgeAccelHannum and AgeAccelPheno was associated with 2.8% (OR: 1.028, 95% CI 1.007-1.049, P = 0.011) and 3.5% (OR: 1.035, 95% CI 1.014-1.056, P = 0.002) increase in CVD risk, respectively. After adjusting confoundings, mediation analysis showed that AgeAccelHannum mediates 10.44% (P = 0.046) of the association between NLR and CVD risk; and AgeAccelPheno mediates 24.03% (P = 0.009) and 18.16% (P = 0.015) of the NLR-CVD and SIRI-CVD risk associations, respectively.</p><p><strong>Conclusion: </strong>Our results demonstrate that EAAs mediate the association between systemic inflammation and CVD risk, highlighting the potential of a multi-target approach to inflammation and epigenetic modifications for personalized management to reduce CVD risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"89"},"PeriodicalIF":4.8,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191566","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":"TERT promoter methylation predicts overall survival, immune cell infiltration and response to immunotherapy in clear cell renal cell carcinoma.","authors":"Xinyu Guan, Jiahao Meng, Wenjun Yi, Kun Ye, Hongyu Gao, Yue Hong, Limeng Qu, Shirong Ding, Qian Long","doi":"10.1186/s13148-025-01897-x","DOIUrl":"10.1186/s13148-025-01897-x","url":null,"abstract":"<p><strong>Purpose: </strong>Telomerase reverse transcriptase (TERT) is one of the most well-established oncogenes in tumor development and progression. It is widely known that TERT promoter hypermethylation is associated with its transcription activation. Despite its canonical role in maintaining telomere length in cancer cells, TERT is also involved in various oncogenic processes independent of its enzymatic activity. However, the role of TERT in the tumor immune microenvironment has been largely unexplored. Hence, we assessed the associations between TERT promoter methylation and its expression, clinicopathological features, overall survival, immune cell infiltration, and response to immune checkpoint inhibitor therapy in clear cell renal cell carcinoma.</p><p><strong>Methods: </strong>A single-sample gene-set enrichment analysis algorithm was used to quantify the relative abundance of each type of immune cell infiltration in the tumor microenvironment (TME) of the TCGA KIRC cohort. We used Spearman's rank correlation to calculate the correlation coefficients between TERT promoter methylation and immune cell infiltration. The relative methylation of cg11625005 in our validation cohort was detected by pyrosequencing and the relative infiltration of CD4 + and CD8 + T cells infiltration in the TME was measured by immunohistochemistry.</p><p><strong>Results: </strong>The TERT promoter was significantly hypermethylated in clear cell renal cell tumor tissues, which was related to the transcriptional activation of TERT. TERT promoter hypermethylation was significantly correlated with aggressive phenotypes and poor survival in clear cell renal cell carcinoma patients. Furthermore, TERT promoter methylation was significantly positively correlated with CD4 + /CD8 + T cells infiltration and immune checkpoint molecule (CTLA-4, TIGIT, PD-1 and LAG3) expression. And TERT promoter methylation was correlated with the therapeutic response to anti-PD1 immunotherapy.</p><p><strong>Conclusion: </strong>TERT promoter methylation is a promising predictive biomarker of immune cell infiltration, overall survival, clinicopathological characteristics and response to anti-PD1 immunotherapy treatment in clear cell renal cell carcinoma patients.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"88"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186722","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":"SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway.","authors":"Junjie Li, Haixia Huang, Yifei Yin, Yizhu Mao, Mengxia Li, Hong Li, Chenxia Jiang, Rongxi Yang","doi":"10.1186/s13148-025-01891-3","DOIUrl":"10.1186/s13148-025-01891-3","url":null,"abstract":"<p><p>Most thyroid nodules can be diagnosed preoperatively by ultrasonography and fine-needle aspiration biopsy. However, accurately differentiating between benign nodules or indolent thyroid tumors and aggressive thyroid cancers remains a significant clinical challenge when the biopsy results are indeterminate. In this study, we aim to explore a novel biomarker to determine the malignancy of thyroid nodules. Fifteen tissue samples from patients with Stage I&II papillary thyroid carcinoma (PTC) and benign thyroid nodule (BTN) were analyzed by EPIC Methylation 850 K and RNA-Sequencing. Altered and inversely correlated methylation and expression in SERPINA1 gene in PTC was found in the discovery study. PTC-associated SERPINA1 hypomethylation was further verified by mass spectrometry in case-control studies from two clinical centers (Validation I: 140 PTCs vs. 182 BTNs, ORs ≥ 2.48, and Validation II: 224 PTCs vs. 217 BTNs, ORs ≥ 2.04; P ≤ 3.07E-15, for all measurable CpG sites). Moreover, SERPINA1 methylation had an outstanding clinical application value to differentiate PTC from BTN (the AUC combining Validation I and Validation II was 0.92). Our study also revealed that the upregulated SERPINA1 could promote cell proliferation, migration and invasion in the PTC cell lines, and thereby facilitate the malignant progression of PTC. Mechanistically, SERPINA1 activated the AKT/mTOR pathway via binding to MAPK6. Intervention targeting either SERPINA1 or MAPK6 has a significant impact on the malignancy of PTC cells. Together, we identified SERPINA1 methylation as a functional and effective diagnostic marker for PTC and provided a novel epigenetic insight into the etiology of PTC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"86"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180437","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 patterns and DNA methylation age acceleration in middle-aged and older Chinese adults.","authors":"Tingyue Diao, Kang Liu, Lue Zhou, Qiuhong Wang, Junrui Lyu, Ziwei Zhu, Fuchao Chen, Wengang Qin, Handong Yang, Chaolong Wang, Xiaomin Zhang, Tangchun Wu","doi":"10.1186/s13148-025-01898-w","DOIUrl":"10.1186/s13148-025-01898-w","url":null,"abstract":"<p><strong>Background: </strong>Sleep is a biological necessity and fundamental to health. However, the associations of sleep patterns (integrating sleep determinants) with DNA methylation age acceleration (DNAm AA) remain unknown. We aimed to investigate the associations of sleep patterns with DNAm AA.</p><p><strong>Methods: </strong>This cross-sectional and prospective cohort study used data from the Dongfeng-Tongji cohort collected from 2013 to December 31, 2018. Sleep patterns were reflected by sleep scores (range 0-4, with higher scores indicating healthier sleep patterns) characterized by bedtime, sleep duration, sleep quality, and midday napping. DNAm AA was estimated by PhenoAge acceleration (PhenoAgeAccel), GrimAge acceleration (GrimAgeAccel), DunedinPACE, and DNAm mortality risk score (DNAm MS). Linear regression models were used to estimate β and 95% confidence intervals (CIs) for the cross-sectional associations between sleep patterns and DNAm AA. Mediation models were applied to assess the mediating role of DNAm AA in the associations between sleep patterns and all-cause mortality in a prospective cohort.</p><p><strong>Results: </strong>Among 3566 participants (mean age 65.5 years), 426 participants died during a mean 5.4-year follow-up. A higher sleep score was associated with lower DNAm AA in a dose-response manner. Each 1-point increase in sleep score was associated with significantly lower PhenoAgeAccel (β = - 0.208; 95% CI - 0.369 to - 0.047), GrimAgeAccel (β = - 0.107; 95% CI - 0.207 to - 0.007), DunedinPACE (β = - 0.008; 95% CI - 0.012 to - 0.004), and DNAm MS (β = - 0.019; 95% CI - 0.030 to - 0.008). Chronological age modified the associations between higher sleep scores and lower PhenoAgeAccel (p for interaction = 0.031) and DunedinPACE (p for interaction = 0.027), with stronger associations observed in older adults. Moreover, a slower DunedinPACE mediated 6.2% (95% CI 0.8% to 11.5%) of the association between a higher sleep score and a lower all-cause mortality risk.</p><p><strong>Conclusion: </strong>In this cohort study, individuals with a higher sleep score had a slower DNAm AA, particularly in older adults. A slower DunedinPACE partially explained the association between higher sleep scores and lower all-cause mortality risk. These findings suggest that adopting healthy sleep patterns may promote healthy aging and further benefit premature mortality prevention, highlighting the value of sleep patterns as a potential tool for clinical management in aging.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"87"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180977","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":"H3K18 lactylation-mediated Ythdf2 activation restrains mouse female germline stem cell proliferation via promoting Ets1 mRNA degradation.","authors":"Yunqiang Wu, Bo Xu, Yonglin Peng, Sang Lin, Wenfei Du, Ruiqi Liu, Shu Zhang, Ji Wu, Kang Zou, Xiaodong Zhao","doi":"10.1186/s13148-025-01890-4","DOIUrl":"10.1186/s13148-025-01890-4","url":null,"abstract":"<p><strong>Background: </strong>Germline stem cells are critical for sustaining fertility by balancing self-renewal and differentiation, and are regulated by genetic and epigenetic programs. Although extensively investigated, the rare female germline stem cells (FGSCs) in mammalian ovaries hinder their application in regenerative medicine. The N⁶-methyladenosine (m⁶A) reader YTHDF2 is required for female germ cell competence. However, the mechanistic underpinnings of how YTHDF2 regulates FGSC proliferation remain elusive.</p><p><strong>Results: </strong>Here, we show that knockout of Ythdf2 enhances FGSC proliferation in vitro. YTHDF2 binds m⁶A-modified Ets1 mRNA and facilitates its degradation in an m⁶A-dependent manner. ETS1 functions as a key downstream effector of YTHDF2, as suppression of ETS1 expression partially reverses the Ythdf2-KO-induced phenotype. Additionally, we demonstrate that YTHDF2/ETS1 axis participates in regulating FGSC proliferation by modulation of proliferation-related gene expression. Moreover, histone lactylation modification H3K18la activates the expression of YTHDF2 in FGSCs.</p><p><strong>Conclusions: </strong>Overall, our study reveals that YTHDF2 intrinsically restrains mouse FGSC proliferation and provides a potential strategy to increase FGSC abundance for its potential clinical application.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"84"},"PeriodicalIF":4.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157135","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":"Cadmium exposure, epigenetic modifications, and serum cystatin C: insights into mediated pathways and mortality risks in U.S. adults.","authors":"Yu-Wei Fang, Ching-Way Chen, Ta-Chen Su, Chien-Yu Lin","doi":"10.1186/s13148-025-01888-y","DOIUrl":"10.1186/s13148-025-01888-y","url":null,"abstract":"<p><strong>Background: </strong>Cadmium exposure has been linked to elevated cystatin C levels, disruptions in epigenetic patterns, and increased mortality risk. However, the role of epigenetic modifications in the relationship between cadmium and cystatin C remains poorly understood. Furthermore, it is unclear how cystatin C and epigenetic changes influence the connection between cadmium exposure and mortality outcomes. The study explored the associations among blood cadmium levels, serum cystatin C, an epigenetic biomarker (DNA methylation-predicted cystatin C, DNAmCystatinC), and mortality outcomes.</p><p><strong>Methods: </strong>We utilized data from 8716 participants aged 18 years and older in the National Health and Nutrition Examination Survey (NHANES, 1999-2002), linked to mortality records from the National Center for Health Statistics (NCHS) through 2019.</p><p><strong>Results: </strong>Our findings revealed that higher natural log-transformed (ln)-blood cadmium was associated with elevated ln-serum cystatin C (β = 0.052, P < 0.001) and higher ln-DNAmCystatinC (β = 0.007, P = 0.008). Compared to the reference group (both blood cadmium and DNAmCystatinC ≤ 50th percentile), those with blood cadmium and DNAmCystatinC > 50th percentile had the highest mean serum cystatin C levels (1.26 mg/L vs. 1.11 mg/L; P for trend = 0.002). Structural equation modeling (SEM) indicated that DNAmCystatinC partially mediated the relationship between cadmium exposure and cystatin C, with a total effect of 0.068, a direct effect of 0.066, and an indirect effect of 0.002. Weighted Cox regression analysis showed higher blood cadmium was associated with an increased risk of all mortality outcomes, with stronger associations observed in individuals whose serum cystatin C was at or above the 50th percentile. These findings were consistent both in the overall population and after excluding individuals with chronic kidney disease. Furthermore, a significant interaction was identified between blood cadmium and serum cystatin C in their influence on all-cause mortality.</p><p><strong>Conclusions: </strong>We found higher blood cadmium is linked to increased serum cystatin C and DNAmCystatinC, with DNAmCystatinC partially mediating the effect on serum cystatin C. Notably, serum cystatin C may modify the relationship between cadmium exposure and mortality outcomes. Further research is warranted to elucidate these complex interactions.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"85"},"PeriodicalIF":4.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157134","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":"Allelic expression patterns of imprinted and non-imprinted genes in cancer cell lines from multiple histologies.","authors":"Julia Krushkal, Travis L Jensen, George Wright, Yingdong Zhao","doi":"10.1186/s13148-025-01883-3","DOIUrl":"10.1186/s13148-025-01883-3","url":null,"abstract":"<p><strong>Background: </strong>Imprinted genes are epigenetically regulated in normal tissues to follow monoallelic expression according to the parent of origin of each allele. Some of these patterns are dysregulated in cancer.</p><p><strong>Results: </strong>We developed a novel computational multi-omic pipeline to evaluate monoallelic and biallelic expression patterns based on matched RNA-seq expression data, whole-exome sequencing information, and copy number data. We analyzed allelic expression of the entire genes, individual isoforms, and each exon of 59,283 autosomal protein-coding and ncRNA genes, with a focus on 94 genes previously reported to be imprinted. We analyzed 108 cell lines from 9 different tumor histologies using molecular data from the DepMap Portal for the Cancer Cell Line Encyclopedia. Allelic expression patterns of imprinted genes and isoforms in tumor cells were variable. We also identified additional genes and isoforms with predominantly monoallelic expression due to a variety of potential mechanisms. We provide a novel public dataset of transcriptome-wide allelic expression patterns in cell lines from diverse tumor categories, which can serve as a resource for future cancer studies. We examined associations of in vitro cell line response to antitumor agents and repurposed drugs with allelic patterns and overall levels of isoform expression of imprinted genes and of additional genes with predominantly monoallelic expression. Drug response was associated with isoform expression patterns of multiple imprinted genes including CPA4, DGCR6, DNMT1, GNAS, GRB10, H19, NAA60, OSBPL5, PHACTR2, and ZFAT, predominantly monoallelically expressed MAP2K5 and BCLAF1, and additional predominantly monoallelically expressed genes. Multiple associations may be related to mechanisms of drug activity, including associations between the response to the DNA damaging agents and allelic expression of ZFAT, CDC27, and BCLAF1 isoforms, and the response to inhibitors of multiple signaling pathways with expression patterns of GNAS isoforms.</p><p><strong>Conclusions: </strong>Tumor cells have a range of monoallelic and biallelic expression patterns in both imprinted and non-imprinted genes and are likely affected by the complex interplay among changes in allelic expression, sequence variants, copy number changes, and expression changes of biologically important genes. Multiple isoform-specific patterns of allelic expression were associated with drug response, indicating complex mechanisms of cancer chemoresistance.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"83"},"PeriodicalIF":4.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141597","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}