Epigenomes最新文献

{"title":"KDM4B Maintains Pyruvate Dehydrogenase Complex Expression to Support Mitochondrial Metabolism and Survival in Cancer Cells.","authors":"Sachiko Sato, Arif Ul Hasan, Mami Obara, Eiichi Taira","doi":"10.3390/epigenomes10030059","DOIUrl":"10.3390/epigenomes10030059","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Metabolic reprogramming is a hallmark of cancer and requires coordinated regulation of glycolysis and mitochondrial metabolism. The pyruvate dehydrogenase complex (PDC) links these pathways by catalyzing the conversion of pyruvate to acetyl-CoA, yet the epigenetic mechanisms regulating PDC expression remain poorly understood. We investigated whether the histone demethylase KDM4B regulates PDC expression and mitochondrial metabolism in cancer cells. <b>Methods:</b> Human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), melanoma (G-361), and non-malignant human proximal tubule epithelial (HK-2) cells were analyzed using glucose-response assays, RNA sequencing, RT-qPCR, immunoblotting, metabolic assays, fluorescence imaging, and cell viability analyses. KDM4B was disrupted by small interfering RNA (siRNA) and the selective inhibitor NCGC00244536. <b>Results:</b> Glucose availability induced coordinated upregulation of the PDC subunits PDHA1, DLD, and DLAT and was associated with increased proliferation and KDM4B expression in cancer cells. Both genetic depletion and pharmacological inhibition of KDM4B suppressed PDC expression and increased the repressive histone mark H3K9me3. Exploratory RNA-seq analysis revealed coordinated metabolic transcriptional reprogramming characterized by induction of glycolytic genes and suppression of PDC, the tricarboxylic acid cycle, and electron transport chain genes, together with increased PDK1 and reduced PDP1 expression, consistent with impaired mitochondrial glucose oxidation. These changes were accompanied by reduced pyruvate dehydrogenase activity, extracellular pyruvate accumulation, ATP depletion, impaired glucose uptake, mitochondrial depolarization, caspase-3 activation, increased lactate dehydrogenase release, reduced viability, and diminished proliferative capacity. These effects were generally more pronounced in the cancer cell models than in HK-2 cells. <b>Conclusions:</b> Our findings identify KDM4B as a regulator associated with maintenance of PDC expression and mitochondrial glucose metabolism in cancer cells. KDM4B inhibition suppresses PDC abundance and activity and is accompanied by metabolic dysfunction, mitochondrial depolarization, and reduced cell survival. These findings support a model in which the KDM4B-PDC axis may contribute to metabolic homeostasis and survival in cancer cells and suggest that this pathway may represent a potential therapeutic vulnerability.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13605158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide DNA Methylation Profiling Reveals Stage- and Severity-Associated Epigenetic Alterations in Children with Posterior Urethral Valve-Associated Chronic Kidney Disease.","authors":"Sachit Anand, Catherine Daise Arokiadas, Ajay Verma, Jitendra Kumar Meena, Chittaranjan Behera, Sandeep Agarwala, Kalpana Luthra","doi":"10.3390/epigenomes10030058","DOIUrl":"10.3390/epigenomes10030058","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is an important cause of morbidity in children, particularly in those with congenital anomalies of the kidney and urinary tract. Although epigenetic alterations have been implicated in CKD, stage-associated genome-wide DNA methylation changes remain poorly characterized in posterior urethral valves (PUV). This study aimed to characterize DNA methylation patterns across CKD stages in children with PUV and identify potential methylation markers associated with CKD severity.</p><p><strong>Methods: </strong>Genome-wide DNA methylation profiling was performed on peripheral blood DNA from 20 boys with PUV stratified by CKD stage and 19 age-matched healthy male controls using the Illumina MethylationEPIC v2.0 array. Analyses included a global stage-wise model, stage-specific comparisons against controls and between CKD stages, an overall PUV-associated CKD-versus-control model, functional enrichment analysis, candidate CKD progression gene analysis, and CKD severity-associated methylation analysis.</p><p><strong>Results: </strong>A global stage-wise analysis identified 11,134 CpG sites showing significant methylation variation across controls and PUV-associated CKD. Differential methylation burden was limited in early CKD stages but increased markedly in advanced CKD, with 4734 and 20,242 DMPs identified in Stage 4 and Stage 5, respectively. DMP-associated genes in advanced CKD stages showed enrichment of immune-related, structural remodeling, and intracellular signaling pathways. Candidate gene analysis identified significant methylation changes in previously reported CKD progression-associated genes, with greater representation in advanced CKD stages. CKD severity-associated analysis identified cg16879596_BC21, annotated to <i>CYP3A5</i>, as positively associated with CKD severity (r = 0.74, FDR = 1.32 × 10^-5). Methylation at this CpG site increased across CKD stages and showed strong internal discrimination between PUV-associated CKD patients and controls (AUC = 0.947, 95% CI = 0.887-1.000).</p><p><strong>Conclusions: </strong>PUV-associated CKD is characterized by stage-associated DNA methylation changes, with a marked increase in methylation burden in advanced CKD stages. The findings highlight immune, structural remodeling, and signaling pathways associated with advanced CKD and identify <i>CYP3A5</i> methylation as a potential marker of CKD severity. In future, larger longitudinal studies with independent validation and functional integration are required.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13605981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth Phase-Related DNA Methylation and Localized DNA Fragment Density Variation in <i>Escherichia coli</i> and <i>Lactobacillus acidophilus</i> Genomes.","authors":"Ziming Chen, Chian Teng Ong, David Chau, Elizabeth M Ross","doi":"10.3390/epigenomes10030057","DOIUrl":"10.3390/epigenomes10030057","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Bacterial DNA methylation is a reversible genetic modification affecting gene regulation without significant DNA sequence alteration, thereby enabling rapid adaptation to various environments. However, traditional motif-based approaches detect DNA methylation at low resolution, limiting the identification of DNA methylation variation and often restricting analysis of multiple methylation forms. <b>Methods:</b> Here, we used Oxford Nanopore Technologies sequencing to examine genome-wide variation in three DNA methylation forms (N6-methyladenine, N4-methylcytosine, and 5-methylcytosine) and DNA fragment density between the exponential and stationary phases of <i>Escherichia coli</i> and <i>Lactobacillus acidophilus</i>. <b>Results:</b> During the exponential phase, regions surrounding the replication terminus displayed lower DNA fragment density in both species and lower 5-methylcytosine levels in <i>Escherichia coli</i>. Methylation calling on each genomic locus revealed almost 21% more differentially methylated sites than motif-based detection. Through the locus-based detection, the majority (72%) of differentially methylated genes in <i>Escherichia coli</i> were differentially expressed. The functions of these genes were associated with the physiological response to growth phase transition, such as cell membrane synthesis and translation. Incorporating multiple DNA methylation forms and including all methylated loci, not just those within common motifs, resulted in higher concordance between differentially expressed genes and differentially methylated genes compared to single-form or motif-based approaches. <b>Conclusions:</b> Our findings suggest that the bacterial DNA methylation pattern is affected by growth phase transition, and that a locus-based differential methylation analysis using Nanopore sequencing can estimate microbial activity in some cases, especially in microbiome studies where the transcriptome-genome link is difficult to establish. <b>Impact Statement:</b> Bacterial DNA methylation is a reversible genetic modification affecting gene regulation, enabling rapid adaptation. There are three major DNA methylation forms in bacteria, namely N6-methyladenine, N4-methylcytosine, and 5-methylcytosine. Using Oxford Nanopore sequencing, we found that DNA methylation levels (N6-methyladenine and 5-methylcytosine) are globally and regionally lower during the exponential phase compared to the stationary phase. Our results showed that differentially methylated genes can robustly estimate the overall transcriptomic profile in <i>Escherichia coli</i>. The inclusion of multiple DNA methylation forms and all methylated loci can improve concordance with differentially expressed genes. Our findings reveal that the bacterial DNA methylation pattern shifts during growth phase transition, and indicate that methylation could be an accessible method for estimating microbial activity.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13605387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Characterization of Epigenetic Regulator Gene Alterations in Juvenile Myelomonocytic Leukemia Through Whole-Exome Sequencing.","authors":"Harsh Goel, Ravi Kumar Majhi, Jagdish Prasad Meena, Anita Chopra, Sameer Bakhshi, Lata Singh, Rachna Seth, Pranay Tanwar, Aditya Kumar Gupta","doi":"10.3390/epigenomes10030056","DOIUrl":"10.3390/epigenomes10030056","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. <b>Methods</b>: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug-gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. <b>Results</b>: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C>T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C>T and T>C transitions, indicating endogenous mutational processes. Analysis of drug-gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. <b>Conclusions</b>: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conserved Partial Reprogramming Effects on the Methylome.","authors":"Elena-Cristina Găitănaru, Roua Gabriela Popescu, Andreea-Angelica Stroe, Sergiu Emil Georgescu, George Cătălin Marinescu","doi":"10.3390/epigenomes10030055","DOIUrl":"10.3390/epigenomes10030055","url":null,"abstract":"<p><strong>Background/objectives: </strong>Among the many proposed theories of aging, a growing body of research points to epigenetic alterations, particularly changes in DNA methylation patterns, as key contributors to biological decline. DNA methylation can be targeted and modulated to induce anti-aging and regenerative effects using an emerging therapeutic approach known as partial reprogramming, induced by different combinations of Yamanaka factors.</p><p><strong>Methods: </strong>In this study, we performed an integrative secondary analysis of five publicly available DNA methylation datasets derived from partial reprogramming experiments across multiple mammalian species, tissues, cell types and combinations of transcription factors (<i>n</i> = 189 samples).</p><p><strong>Results: </strong>Following differential methylation analysis of 929,009 CpGs, we identified 14 CpG sites showing reproducible and significant changes, with two CpGs consistently present across all datasets.</p><p><strong>Conclusions: </strong>These findings suggest that partial reprogramming may exert anti-aging and regenerative effects, in part, through the selective modulation of conserved DNA methylation sites.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Changes in Inflammation-Related Methylation Risk Score for C-Reactive Protein Among People with HIV.","authors":"Yijie Huang, Junyu Chen, Alexandra Young, Qin Hui, Johnathan A Edwards, Alec Powers, Matthew R Dudgeon, Selvan Pillay, Jaysingh Brijkumar, Mahomed Y S Moosa, Marta Gwinn, Viola Vaccarino, Vincent C Marconi, Yan V Sun","doi":"10.3390/epigenomes10030054","DOIUrl":"10.3390/epigenomes10030054","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Human immunodeficiency virus (HIV) infection is characterized by chronic systemic inflammation. Antiretroviral therapy (ART) can reduce persistent inflammation, as measured by C-reactive protein (CRP). The CRP methylation risk score (MRS_CRP) acts as proxy for plasma CRP, but longitudinal changes in this score for people with HIV (PWH) before and after initiating ART have not been described. <b>Methods</b>: We evaluated a previously published MRS_CRP in the Emory Twin Study (N = 352), testing its correlation with plasma CRP and CRP-responsive biomarkers, as well as associations with cardiometabolic traits using generalized estimating equations (GEEs). We then applied MRS_CRP in the HIV AIDS Drug Resistance Surveillance Study (ADReSS) cohort (N = 440) to assess longitudinal changes before and after ART, using paired <i>t</i>-tests and linear mixed-effects models. <b>Results</b>: MRS_CRP showed moderate correlation with CRP (r = 0.38) and other inflammatory biomarkers (r = 0.25-0.34). MRS_CRP was associated with hypertension, type 2 diabetes, coronary artery disease, and obesity, and remained independently associated with obesity (odds ratio = 1.49) after adjusting for measured CRP. Z-score-standardized MRS_CRP decreased by 0.254 standard deviation units between baseline and follow-up among PWH receiving ART, confirmed by linear mixed-effects models. <b>Conclusions</b>: MRS_CRP showed associations with chronic inflammation and cardiometabolic diseases. The observed decline in MRS_CRP following ART initiation may reflect changes in inflammatory status among PWH. These findings highlight the potential of MRS_CRP as a marker of inflammation-related changes and comorbidity risk in PWH.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Epigenomics: Bioinformatics Strategies for Multi-Omics Data Analysis in Health and Disease.","authors":"Shikhi Baruri, Lalit Batra, Sohome Adhikari, Ayman El-Baz","doi":"10.3390/epigenomes10030053","DOIUrl":"10.3390/epigenomes10030053","url":null,"abstract":"<p><p><b>Background:</b> Epigenomics has emerged as an essential field in modern molecular biology, providing a critical layer of gene regulation. DNA methylation, histone modifications and alterations to the chromatin accessibility of DNA have been widely associated with complex diseases including cancer. The most recent developments in high-throughput sequencing technology have made it possible to profile epigenetic landscapes genomically on a large scale. However, bulk averaging can obscure cellular heterogeneity essential for understanding complex disease states. The purpose of the review is to survey accessible tools and algorithms to conduct an Epigenomic study in the field of biomedical research, from bulk tissue analysis to the high-resolution frontier of single-cell epigenomics. <b>Methods:</b> We performed a comparative analysis of common methods used to analyze DNA methylation, chromatin immunoprecipitation, sequencing analysis and chromatin accessibility profiling. We described the standardized bioinformatics tools and pipelines required to transform raw sequencing data into mechanistic biological understanding, highlighting the role of quality control, peak calling, and differential analysis. Furthermore, we explore the integration of epigenomics with other \"omics\" layers through advanced computational frameworks, including machine learning and network-based modeling. <b>Results:</b> These advanced multi-omics techniques demonstrate promising clinical utility by enabling biomarker discovery, disease subtyping, and identification of novel therapeutic targets. <b>Conclusions:</b> Despite challenges with data complexity, the fusion of Artificial Intelligence (AI) and single-cell technologies will accelerate the transition toward precision medicine.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Memory and Hormonal Crosstalk in Plant Drought Adaptation: Mechanisms, miRNAs, and Technological Advances.","authors":"Emanuela Talarico, Eleonora Greco, Marina Camoli, Francesco Guarasci, Cristina Teruzzi, Fabrizio Araniti, Leonardo Bruno","doi":"10.3390/epigenomes10030052","DOIUrl":"10.3390/epigenomes10030052","url":null,"abstract":"<p><p>Drought poses a major threat to global food security, making it critical to understand the molecular mechanisms underlying plant responses to water scarcity. Epigenetic modifications, including DNA methylation and histone alterations, play central roles in regulating genes and hormonal pathways essential for drought adaptation. MicroRNAs, while primarily functioning as post-transcriptional regulators, can also influence epigenetic pathways and contribute to chromatin remodelling, suggesting a role in modulating epigenetic memory. Investigating these interactions is essential for understanding how plants integrate epigenetic and post-transcriptional regulation during stress. Epigenetic memory in drought-adapted plants provides insights into the transgenerational inheritance of adaptive traits and reveals how plants balance genome stability with flexibility. The crosstalk between epigenetic mechanisms and hormonal signalling is crucial for fine-tuning gene expression, promoting drought resilience. This review proposes a conceptual framework integrating epigenetic, hormonal, and miRNA-mediated regulation of drought responses. It emphasizes the impact of advanced technologies, such as bisulfite sequencing and CRISPR-Cas9, in dissecting plant epigenetic responses to drought. These approaches improve our understanding of drought tolerance mechanisms and offer promising strategies for developing resilient crops for sustainable agriculture. However, direct evidence linking epitranscriptomic modifications to long-term drought memory remains limited, and this emerging regulatory layer requires further experimental validation.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cord Blood DNA Methylation and Large-for-Gestational-Age Birth: A Pilot Epigenome-Wide Study in the GROW Cohort.","authors":"Xiaoyu Liang, Christopher Doumith, Dawn P Misra, Vinod K Misra","doi":"10.3390/epigenomes10030051","DOIUrl":"10.3390/epigenomes10030051","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Large-for-gestational-age (LGA) birth is associated with adverse perinatal outcomes and increased risk of metabolic disease later in life. Despite these risks, epigenetic studies of LGA remain limited, particularly those using umbilical cord blood DNA methylation (DNAm) as the tissue of interest. <b>Methods:</b> We conducted an epigenome-wide association study of cord blood DNAm in a nested case-control sample from the Gestational Regulators of Weight (GROW) cohort. The analysis included 28 term LGA infants and 63 term appropriate-for-gestational-age (AGA) controls. DNAm was measured using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analyses were performed with adjustment for residual principal components and estimated cord blood cell-type proportions. <b>Results:</b> No CpG sites reached statistical significance after false discovery rate correction. Twenty-four CpGs showed nominal associations with LGA status at <i>p</i>-value < 1.00 × 10^-4, including five CpGs with absolute methylation differences greater than 0.05. Among annotated loci, the strongest interpretable signals included cg06750897 in <i>PBX1</i> (Δβ = 0.110, <i>p</i>-value = 1.70 × 10^-5) and two nearby CpGs in <i>SMAD3</i>, cg23731272 (Δβ = 0.111, <i>p</i>-value = 4.31 × 10^-5) and cg02486855 (Δβ = 0.109, <i>p</i>-value = 9.45 × 10^-5). These two <i>SMAD3</i> CpGs showed concordant hypermethylation in LGA infants and formed a candidate regional methylation signal in exploratory targeted regional analysis. <b>Conclusions:</b> In this pilot study, LGA was associated with modest cord blood DNAm differences, although no CpG sites reached genome-wide significance. The strongest interpretable signals involved <i>PBX1</i> and <i>SMAD3</i>, suggesting candidate loci for further evaluation in larger studies of fetal overgrowth.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Methylation in Neurobiological Genes Associated with Problematic Digital Use in Adolescents and Young Adults: Systematic Review and Exploratory Multilevel Meta-Analysis of Emerging Evidence.","authors":"Héctor Cabezas-Klinger, Fabián Felipe Fernández-Daza, Yecid Mina-Paz","doi":"10.3390/epigenomes10030050","DOIUrl":"10.3390/epigenomes10030050","url":null,"abstract":"<p><strong>Background: </strong>Problematic digital use in adolescents and young adults has emerged as a relevant exposure for mental health and neurobiological vulnerability. However, its relationship with peripheral DNA methylation differences in neurobiologically relevant genes remains poorly synthesized.</p><p><strong>Objective: </strong>This systematic review and exploratory multilevel meta-analysis aimed to synthesize available scientific evidence on associations between phenotypes of problematic internet or smartphone use and DNA methylation differences in neurobiologically relevant genes, and to quantitatively explore the average magnitude of these associations from available data.</p><p><strong>Methods: </strong>Primary human studies were identified through a search strategy with no initial publication-year restriction; the eligible studies retrieved and included in the review were published between 2018 and 2024. The review followed PRISMA criteria and a broad, predefined eligibility strategy to capture both direct and indirect evidence. Seven studies were included in the systematic review; four provided quantifiable data for statistical synthesis, from which 41 effect sizes were harmonized. Analyses were performed in R using multilevel meta-analysis and meta-regression models with REML estimation, supplemented by sensitivity analyses with robust variance estimation.</p><p><strong>Results: </strong>The main meta-analysis revealed a significant positive association between problematic digital exposure and DNA methylation differences (Fisher's z = 0.2957; r = 0.287; 95% CI [0.1146, 0.4769]; <i>p</i> = 0.0020), with high heterogeneity (total I² = 93.15%). Meta-regression indicated that the type of effect and the biological direction of the finding explained a substantial proportion of the observed heterogeneity (total R² ≈ 97.4%).</p><p><strong>Significance: </strong>These findings should be interpreted as exploratory evidence of a biologically plausible association between problematic digital exposure and peripheral DNA methylation differences in neurobiologically relevant genes, rather than as causal or clinically validated biomarker evidence. The available evidence remains methodologically heterogeneous, preliminary, and dependent on a small number of independent studies, underscoring the need for larger, longitudinal, and more methodologically rigorous research in this field.</p>","PeriodicalId":55768,"journal":{"name":"Epigenomes","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13511636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}