Clinical Epigenetics最新文献

{"title":"LSD1 is a targetable vulnerability in gastric cancer harboring TP53 frameshift mutations.","authors":"Suzeng Wang, Chunyu Yang, Junhui Tang, Kaiqing Wang, Hao Cheng, Surui Yao, Zhaohui Huang, Bojian Fei","doi":"10.1186/s13148-025-01829-9","DOIUrl":"10.1186/s13148-025-01829-9","url":null,"abstract":"<p><strong>Background: </strong>TP53 mutations are linked to aggressive progression and chemoresistance in gastric cancer (GC). Frameshift mutation is the second most common mutation type of TP53. However, the consequences of this mutation type in GC were not well understood, and targeted therapies for cancer patients harboring frameshift mutations were also not established. Histone methylation significantly influences tumorigenesis in TP53-mutated cancers, and related inhibitors are emerging as specific therapeutic strategies.</p><p><strong>Methods and results: </strong>By treating GC cell lines harboring various TP53 mutation types with a library of histone demethylase inhibitors, we identified that GSK690, a reversible inhibitor of lysine-specific demethylase 1 (LSD1), selectively inhibits GC cells harboring TP53 frameshift mutations without nuclear localization sequence (NLS) (termed TP53 Frameshift ^NLS), which accounts for 89% TP53 frameshift mutations in GC patients. GSK690 showed significant specific inhibition in vitro and in vivo against this subtype by inducing G1/S cell cycle arrest via the LSD1-CCNA2 axis. Importantly, dual-luciferase assays and ChIP-qPCR confirmed that the loss of transcriptional repression activities of p53 in drives LSD1 upregulation in TP53 Frameshift ^NLS cancer cells.</p><p><strong>Conclusions: </strong>In summary, our results indicate that the nuclear localization deficiency of p53 accounts for increased expression of LSD1 in TP53 Frameshift ^NLS GCs. GSK690 inhibits cell cycle progression and tumor growth by suppressing aberrantly activated LSD1-CCNA2 signaling in this GC subtype, counteracting malignant proliferation and thereby providing a precise therapeutic strategy for GC patients with TP53 Frameshift ^NLS.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"26"},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448400","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":"Radiogenomic method combining DNA methylation profiles and magnetic resonance imaging radiomics predicts patient prognosis in skull base chordoma.","authors":"Xiaoyu Deng, Peiran Li, Kaibing Tian, Fan Zhang, Yumeng Yan, Yanghua Fan, Zhen Wu, Junting Zhang, Jiang Du, Wei Chen, Liang Wang","doi":"10.1186/s13148-025-01836-w","DOIUrl":"10.1186/s13148-025-01836-w","url":null,"abstract":"<p><strong>Background: </strong>Chordoma is a rare malignant bone tumor exhibiting poor survival and prognosis. Hence, it is crucial to develop a convenient and effective prognostic classification method for the rehabilitation and management of patients with chordoma. In this study, we combined DNA methylation profiles and magnetic resonance imaging (MRI) images to generate a radiogenomic signature to assess its effectiveness for prognosis classification in patients with skull base chordoma.</p><p><strong>Results: </strong>DNA methylation profiles from chordoma tissue samples of 40 patients were factorized into eight DNA methylation signatures. Among them, Signature 4 was identified as the prognosis-specific signature. Based on the Signature 4 loading values, the patients were categorized into low-signature (LLG) and high-signature (HLG) loading groups. HLG patients had higher progression-free survival times than LLG patients. Combined analysis with external single-cell RNA-seq data revealed higher tumor cell proportions and lower natural killer cell proportions in the HLG than in the LLG. Additionally, 2,553 radiomic features were extracted from T1, T2, and enhanced T1 MRI images of the patients, and a radiogenomic signature comprising 14 radiomic features was developed. In a validation cohort of 122 patients, the radiogenomic signature successfully distinguished between the two groups (P = 0.027). Furthermore, the existence of Signature 4 was confirmed in an additional dataset of 14 patients.</p><p><strong>Conclusion: </strong>We developed a prognostic radiogenomic signature using a radiogenomic classification method, which leverages MRI images to extract features that reflect the DNA methylation signature associated with prognosis, enabling the stratification of patients based on their prognostic risk. This method offers the advantages of being noninvasive and convenient.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"23"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440193","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":"Identification of 17 novel epigenetic biomarkers associated with anxiety disorders using differential methylation analysis followed by machine learning-based validation.","authors":"Yoonsung Kwon, Asta Blazyte, Yeonsu Jeon, Yeo Jin Kim, Kyungwhan An, Sungwon Jeon, Hyojung Ryu, Dong-Hyun Shin, Jihye Ahn, Hyojin Um, Younghui Kang, Hyebin Bak, Byoung-Chul Kim, Semin Lee, Hyung-Tae Jung, Eun-Seok Shin, Jong Bhak","doi":"10.1186/s13148-025-01819-x","DOIUrl":"10.1186/s13148-025-01819-x","url":null,"abstract":"<p><strong>Background: </strong>The changes in DNA methylation patterns may reflect both physical and mental well-being, the latter being a relatively unexplored avenue in terms of clinical utility for psychiatric disorders. In this study, our objective was to identify the methylation-based biomarkers for anxiety disorders and subsequently validate their reliability.</p><p><strong>Methods: </strong>A comparative differential methylation analysis was performed on whole blood samples from 94 anxiety disorder patients and 296 control samples using targeted bisulfite sequencing. Subsequent validation of identified biomarkers employed an artificial intelligence-based risk prediction models: a linear calculation-based methylation risk score model and two tree-based machine learning models: Random Forest and XGBoost.</p><p><strong>Results: </strong>Seventeen novel epigenetic methylation biomarkers were identified to be associated with anxiety disorders. These biomarkers were predominantly localized near CpG islands, and they were associated with two distinct biological processes: 1) cell apoptosis and mitochondrial dysfunction and 2) the regulation of neurosignaling. We further developed a robust diagnostic risk prediction system to classify anxiety disorders from healthy controls using the 17 biomarkers. Machine learning validation confirmed the robustness of our biomarker set, with XGBoost as the best-performing algorithm, an area under the curve of 0.876.</p><p><strong>Conclusion: </strong>Our findings support the potential of blood liquid biopsy in enhancing the clinical utility of anxiety disorder diagnostics. This unique set of epigenetic biomarkers holds the potential for early diagnosis, prediction of treatment efficacy, continuous monitoring, health screening, and the delivery of personalized therapeutic interventions for individuals affected by anxiety disorders.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"24"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440190","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":"HOXA9 methylation is not associated with survival in Brazilian patients with lung adenocarcinoma.","authors":"Anna Luiza Silva Almeida Vicente, Fabiana Aparecida de Souza Santos, Welinton Yoshio Hirai, Delphine Lissa, Rodrigo de Oliveira Cavagna, Aline Larissa Virginio da Silva, Mariana Bisarro Dos Reis, Eduardo Caetano Albino da Silva, Flávio Augusto Ferreira da Silva, Josiane Dias Mourão, Pedro De Marchi, Ana Carolina de Carvalho, Letícia Ferro Leal, Rui Manuel Reis","doi":"10.1186/s13148-025-01831-1","DOIUrl":"10.1186/s13148-025-01831-1","url":null,"abstract":"<p><p>Homeobox A9 promoter methylation (HOXA9) has been reported as a biomarker for early lung adenocarcinoma patients' prognosis. We aim to evaluate its prognostic value, regardless of disease stage. Using droplet digital PCR, we measured HOXA9 methylation in a cohort comprising 161 Brazilian patients. Low HOXA9 methylation was associated with higher cancer-specific survival but showed no significance after adjustment for clinical covariates. While low HOXA9 methylation was associated with earlier stages, no survival association was observed in this subset of patients. Overall, HOXA9 promoter methylation is not an independent prognostic biomarker of cancer-specific survival in Brazilian lung adenocarcinomas patients.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"25"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440186","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-based telomere length is more strongly associated with long-term all-cause mortality than quantitative polymerase chain reaction-based telomere length among middle-aged and older hypertensive adults.","authors":"Qianhui Wang, Yuanfeng Gao, Dilare Taiwaikuli, Huanhuan Ding, Jie Song, Xinchun Yang, Baopeng Tang, Xianhui Zhou","doi":"10.1186/s13148-025-01833-z","DOIUrl":"10.1186/s13148-025-01833-z","url":null,"abstract":"<p><strong>Background: </strong>Telomere length (TL) has been linked to mortality risk across various populations. However, its predictive value for mortality risk specifically in hypertensive adults remains unclear.</p><p><strong>Methods: </strong>This cohort study utilized data from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES). TL was assessed using DNA methylation (DNAmTL) and quantitative polymerase chain reaction (qPCRTL). Cox proportional hazards models were employed to examine the relationship between TL and mortality risk.</p><p><strong>Results: </strong>This study included 1601 participants, with 988 deaths occurring during a median follow-up of 184 months, including 279 from cardiovascular disease (CVD). Deceased participants exhibited significantly lower levels of DNAmTL (6.45 ± 0.30 vs. 6.70 ± 0.28, P < 0.001) and qPCRTL (0.89 ± 0.22 vs. 0.99 ± 0.24, P < 0.001) compared to survivors. After full adjustment, each 1-kb decrement in DNAmTL and qPCRTL was associated with a 52% and 38% reduction in all-cause mortality risk, respectively. Participants in the highest TL quartile (Q4) for DNAmTL and qPCRTL had a 36% and 25% reduced risk of all-cause mortality than those in the lowest quartile (Q1), respectively. Receiver operating characteristic (ROC) curves demonstrated that DNAmTL had superior predictive value compared to qPCRTL (area under curve [AUC] 0.73 vs. 0.63, P < 0.001).</p><p><strong>Conclusion: </strong>TL is inversely associated with all-cause mortality risk in middle-aged and older hypertensive adults, with DNAmTL showing greater predictive accuracy for long-term mortality than qPCRTL.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"22"},"PeriodicalIF":4.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425029","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":"Sex-specific role of epigenetic modification of a leptin upstream enhancer in adipose tissue.","authors":"Luise Müller, Rebecca Oelkrug, Jens Mittag, Anne Hoffmann, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Esther Guiu Jurado, Nora Klöting, Arne Dietrich, Matthias Blüher, Peter Kovacs, Kerstin Krause, Maria Keller","doi":"10.1186/s13148-025-01830-2","DOIUrl":"10.1186/s13148-025-01830-2","url":null,"abstract":"<p><strong>Objective: </strong>Maternal hormonal status can have long-term effects on offspring metabolic health and is likely regulated via epigenetic mechanisms. We elucidated the effects of maternal thyroid hormones on the epigenetic regulation of leptin (Lep) transcription in adipose tissue (AT) and subsequently investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology.</p><p><strong>Results: </strong>Pregnant mice treated with triiodothyronine (T3) produced offspring with reduced body weight, total fat mass, and gonadal white adipose tissue (gWAT) mass at 6 months of age (treatment: N = 8; control: N = 12). Compared with control offspring, exclusively female offspring of T3-treated mothers presented lower Lep mRNA levels and higher Lep UE methylation in gWAT. In murine preadipocytes, targeted demethylation of the Lep UE via a dCas9-SunTag-TET1 system reduced methylation by ~ 20%, but this effect was insufficient to alter Lep expression or lipid accumulation after differentiation. In human omental visceral AT (OVAT) samples from the Leipzig Obesity BioBank (LOBB, N = 52), LEP UE methylation was associated with body fat percentage, and mediation analysis indicated that leptin serum levels partially mediate this association exclusively in females.</p><p><strong>Conclusion: </strong>Findings from the animal model suggest that maternal thyroid hormones influence offspring gWAT Lep expression in a sex-specific manner, potentially through changes in Lep UE methylation. However, in vitro experiments indicate that Lep UE methylation alone is not sufficient to regulate Lep expression or adipocyte lipid accumulation. In humans with obesity, LEP UE methylation is associated with body fat percentage, with leptin serum levels potentially acting as a mediator exclusively in females.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"21"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398536","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":"Vitrification affects the post-implantation development of mouse embryos by inducing DNA damage and epigenetic modifications.","authors":"Yurong Chen, Haibo Zhu, Fucheng Guo, Luyao Wang, Wenli Zhang, Ruizhi Liu, Xiaoling Zhang, Xiangpeng Dai","doi":"10.1186/s13148-025-01826-y","DOIUrl":"10.1186/s13148-025-01826-y","url":null,"abstract":"<p><p>Vitrification is widely used in assisted reproductive technology (ART) for female infertility, but the long-term effect on the embryo of vitrification has not been comprehensively studied. The study aimed to investigate the effect of vitrification on long-term development of mouse embryos. The warmed embryos which were frozen at 8-cell stage were cultured in vitro until the blastocyst stage and were transferred into recipients. Immunofluorescence staining was performed to evaluate the reactive oxygen species (ROS) level, mitochondrial function, cell apoptosis, DNA damage and histone epigenetic modification in blastocysts. Transmission electron microscopy (TEM) analysis was performed to exam the mitochondrial ultrastructure in blastocysts. The related gene expression and transcriptome profiles were investigated by RT-qPCR and RNA-seq, respectively. Blastocyst and implantation frequencies were not significantly affected by vitrification. However, vitrification significantly reduced blastocyst cell number and the live pup frequency. Vitrification induced ROS accumulation, DNA damage, and apoptosis in mouse blastocysts. The homologous recombination (NHEJ) is the major DNA repair pathway for vitrified embryos. Vitrification elevated H3K4me2/3, H4K12ac, and H4K16ac levels and reduced m⁶A modification in blastocysts. Moreover, vitrification significantly altered transcriptome profiles of mice placentas and brains at embryonic day 18.5 (E18.5). Thus, vitrification exhibited a long-term effect on mouse embryo viability by increasing ROS levels, DNA damage, altering the epigenetic modifications and transcriptome profiles.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"20"},"PeriodicalIF":4.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370384","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":"Longitudinal maternal glycemia during pregnancy and placental epigenetic age acceleration.","authors":"Tesfa Dejenie Habtewold, Prabhavi Wijesiriwardhana, Richard J Biedrzycki, Cuilin Zhang, Katherine L Grantz, Jagteshwar Grewal, Fasil Tekola-Ayele","doi":"10.1186/s13148-025-01825-z","DOIUrl":"10.1186/s13148-025-01825-z","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of maternal glucose homeostasis has been related to an increased risk of morbidity and mortality in mothers and fetuses, yet the mechanism remains unclear. This study investigated the association between maternal glycemic levels and placental epigenetic age acceleration (PAA) in a multiethnic cohort.</p><p><strong>Methods: </strong>In a sample of 301 pregnant women (102 Hispanic, 77 White, 72 Black, and 50 Asian/Pacific Islander), the association of glycemic markers cumulative exposure with PAA was tested using linear regression adjusting for fetal sex, maternal age, educational status, and health insurance status. Models were applied in the full cohort and stratified by race/ethnicity. Further, sensitivity analyses were performed after excluding women with GDM or preeclampsia.</p><p><strong>Results: </strong>Among Black women, high glucose, HbA1c, and insulin cumulative exposure levels were associated with lower PAA compared to low cumulative exposure levels (β = - 0.75 weeks, 95% CI = - 1.41 to - 0.08); β = - 0.86, 95% CI = - 1.51 to - 0.21; and β = - 0.76, 95% CI = - 1.49 to - 0.03, respectively). Among Asian/Pacific Islander women, medium insulin cumulative exposure level was associated with lower PAA (β = - 0.94 weeks, 95% CI = - 1.74 to - 0.14). No significant association was observed among White and Hispanic women as well as in the full cohort.</p><p><strong>Conclusions: </strong>Elevated glucose, HbA1c, and insulin cumulative levels throughout pregnancy were associated with lower PAA in Black and Asian/Pacific Islander women. Placental epigenetic aging may be altered by maternal elevated glycemia and may in part underlie early programming of health outcomes in pregnancy and childhood health outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"19"},"PeriodicalIF":4.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363958","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":"miR-182 promoter hypermethylation predicts the better outcome of AML patients treated with AZA + VEN in a real-world setting.","authors":"Yilan Xu, Danyang Li, Na Wang, Bei Ge, Chen Meng, Min Zhao, Zihan Lin, Min Li, Yigang Yuan, Yue Cai, Liuzhi Shi, Shenmeng Gao, Haige Ye","doi":"10.1186/s13148-025-01823-1","DOIUrl":"10.1186/s13148-025-01823-1","url":null,"abstract":"<p><strong>Background: </strong>5-Azacytidine (AZA) combined with the BCL2 inhibitor Venetoclax (VEN) is the standard treatment for elderly acute myeloid leukemia (AML) patients or those who are unfit for intensive chemotherapy (elderly or unfit AML). However, an effective and rapid predictive biomarker to predict treatment outcome remains elusive.</p><p><strong>Methods: </strong>miR-182 promoter methylation was measured in 94 AZA + VEN-treated elderly or unfit AML patients and 20 normal controls (NCs) samples. To determine whether miR-182 promoter methylation is a predictive marker of clinical outcomes in AZA + VEN-treated AML patients in a real-world setting, we analyzed and compared the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate, overall survival (OS), and leukemia free-survival (LFS) across different methylation groups: miR-182 promoter hypomethylation (median value < 20.21%) and hypermethylation (> 20.21%) in a retrospective study.</p><p><strong>Results: </strong>The average methylation frequency was markedly higher in 94 AZA + VEN-treated elderly or unfit AML patients than that in 20 NCs. However, some AML patients (11.7%) still presented low miR-182 promoter methylation (< 10%). The average time to obtain CR/CRi was shorter in AML patients with miR-182 promoter hypermethylation than AML with hypomethylation. Moreover, the median OS and LFS were longer in AML patients with miR-182 promoter hypermethylation than AML with hypomethylation. Finally, the area under the curve (AUC) for 1-year mortality was 0.831, for 2-year was 0.788, and for 3-year was 0.800.</p><p><strong>Conclusions: </strong>AML patients with miR-182 promoter hypermethylation have better outcomes. miR-182 promoter methylation is a predictive biomarker for AZA + VEN-treated AML patients.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"18"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254848","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":"Age-related changes in DNA methylation in a sample of elderly Brazilians.","authors":"Hayley Welsh, Caio M P F Batalha, Weili Li, Nadja C Souza-Pinto, Yeda A O Duarte, Michel S Naslavsky, Esteban J Parra","doi":"10.1186/s13148-025-01821-3","DOIUrl":"10.1186/s13148-025-01821-3","url":null,"abstract":"<p><strong>Background: </strong>Age-related changes in DNA methylation (DNAm) play a critical role in regulating gene expression. However, most epigenome-wide association studies have predominantly focused on individuals of European descent. This study aims to characterize longitudinal changes in DNAm patterns in a cohort of elderly Brazilian participants.</p><p><strong>Methods: </strong>DNAm profiles were collected approximately nine years apart from 23 elderly Brazilian individuals using the Illumina Infinium MethyationEPIC BeadChip. Using mixed-effects models, we examined changes in DNAm patterns using both quantitative age and binary timepoint (e.g., baseline vs. follow-up) as predictors of interest to identify differentially methylated positions (DMPs). Significant DMPs were compared with a list of previously identified age-related DMPs. Differentially methylated regions (DMRs) were also identified using DMRcate. Gene ontology (GO) pathway enrichment analyses were performed to explore the functional significance of identified DMPs and DMRs.</p><p><strong>Results: </strong>Of the 586,229 autosomal probes included in the differential methylation analyses, 2768 significant (FDR < 0.05) age-associated DMPs (aDMPs) and 2757 significant (FDR < 0.05) timepoint-associated DMPs (tpDMPs) were identified. Of the 2768 aDMPs, 1471 were replicated from previous studies. Of the 1297 non-replicated CpGs, 77.4% were exclusive to the EPIC array. The DMR analyses identified 305 age-associated DMRs (aDMRs) and 372 timepoint-associated DMRs (tpDMRs). Both aDMPs and aDMRs exhibited age-related hypermethylation within CpG islands and promoter regions of the genome, whereas hypomethylation predominantly occurred in interCGI and intergenic regions and introns. The GO enrichment analyses identified several neurological and cognition-related pathways enriched for hypermethylated CpG islands, many of which were mapped near transcription start sites and first exon regions.</p><p><strong>Conclusions: </strong>This longitudinal study identified age-associated and timepoint-associated DMPs and DMRs in a sample of elderly Brazilians. Most of the non-replicated CpGs were found to be on the new EPIC array, suggesting that more age-related studies using the EPIC array are required to validate these CpGs. The GO pathway enrichment analyses identified age-related enrichment of several gene sets related to cognitive and physical decline in elderly populations. The enrichment of these sites could provide evidence for age-related neurodegeneration and cognitive decline in elderly populations.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"17"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254843","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}