Frontiers in epigenetics and epigenomics最新文献

{"title":"Epigenetic profiling of preterm birth: a dual-tissue methylation patterns using long-read sequencing.","authors":"BalaSubramani Gattu Linga, Faisal E Ibrahim, Aleem Razzaq, Muthanna Samara, Jameela Roshanuddin, Hind H Adi, Aseel Al-Dewik, Ayla J Ahmedoglu, Rand Hamdan, Amal E I Ahmed, M Walid Qoronfleh, Hatem Zayed, Duaa Elshiekh, Mona Ellaithi, Mohamed Alsharshani, Palli Valapila Abdulrouf, Thomas Farrell, Bader Kurdi, Ghassan Abdoh, Hilal Al Rifai, Nader Al-Dewik","doi":"10.3389/freae.2025.1644521","DOIUrl":"10.3389/freae.2025.1644521","url":null,"abstract":"<p><strong>Introduction: </strong>Preterm birth (PTB), a leading cause of neonatal morbidity and mortality, arises from complex maternal-fetal interactions with multifactorial origins. Emerging evidence suggests that epigenetic dysregulation may mediate these interactions. This study aimed to identify DNA methylation changes associated with PTB to uncover potential biomarkers and underlying mechanisms.</p><p><strong>Methods: </strong>We employed long-read sequencing to profile genome-wide DNA methylation followed by gene ontology and pathway enrichment analysis in matched maternal peripheral blood and neonatal cord blood from 15 preterm and 7 full-term deliveries (mother-infant pairs).</p><p><strong>Results: </strong>A total of 1,151 significantly differentially methylated regions (DMRs) and 25,336 differentially methylated loci (DMLs) were identified across maternal and neonatal blood samples. In maternal blood from PTB cases, the most significantly hypermethylated genes were <i>MED38</i>, <i>PSMB11</i>, and <i>WNT7B</i>, whereas <i>EXTL3</i> and <i>MMP9</i> were among the most hypomethylated. Additionally, the promoters of <i>VWA5A</i>, <i>EIF4E3</i>, <i>ZNF571</i>, and <i>COPB2</i> exhibited significant hypermethylation, while those of <i>SIRPB1</i> and <i>TNFRSF19</i> showed hypomethylation. In neonatal cord blood from PTB cases, the most significantly hypermethylated genes were <i>LOC401478</i>, <i>ISG20</i>, <i>LMTK3</i>, <i>TCAF2</i>, and <i>COL4A2</i>, whereas <i>EXTL3</i> and <i>MMP9</i> were among the most hypomethylated. Promoters of <i>DKK3</i>, <i>CELF2</i>, and <i>IFI35</i> were notably hypermethylated, whereas <i>ALOX12</i> and <i>CLBA1</i> were among the most hypomethylated. Enrichment analysis revealed that these epigenetic alterations impact critical developmental, immune, and neuroendocrine pathways, including Wnt signaling, calcium signaling, MAPK, oxytocin signaling, and neuroactive ligand-receptor interaction. Comparative analysis identified 120 overlapping DMLs, with 91 hypermethylated and 28 hypomethylated consistently across maternal and neonatal samples, including <i>DPPA3</i>, <i>ABCA1</i>, and <i>GKN1</i>. In contrast, 20,240 and 4,770 DMLs were unique to cord and peripheral blood, respectively. Additionally, 14 overlapping DMRs were mapped to genes such as <i>PLD5</i>, <i>FBXO40</i>, <i>GMNC</i>, <i>HHIP</i>, <i>CLEC18B</i>, and <i>LHX1</i>, exhibiting non-random chromosomal clustering. Enrichment analysis of these shared DMRs revealed significant involvement in developmental processes, including skeletal morphogenesis, axis patterning, and fibroblast growth factor signaling, indicating convergence on core regulatory pathways in PTB.</p><p><strong>Conclusion: </strong>This is the first dual-tissue PTB study using long-read methylation profiling. Our results reveal distinct and shared epigenetic signatures in maternal and neonatal compartments, offering insights into the molecular etiology of PTB and potential biomarke","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1644521"},"PeriodicalIF":0.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121915","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 dysregulation in pancreatic cancer: emerging biomarkers and clinical applications.","authors":"Hina Sultana, Abhishikt David Solomon, Atif Khurshid Wani, Surendra K Shukla","doi":"10.3389/freae.2025.1723159","DOIUrl":"10.3389/freae.2025.1723159","url":null,"abstract":"<p><p>Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal malignancies with delayed diagnosis, aggressive nature, and profound therapeutic resistance. Recent research has emphasized epigenetic dysregulation not as a bystander but as a driving force in pancreatic tumorigenesis, progression, metastasis, and immune evasion. This review presents a detailed analysis of the multifaceted functions of epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs in shaping the pancreatic cancer epigenome. We discuss how these alterations fuel tumor heterogeneity, modulate the tumor microenvironment, and interact with key oncogenic mutations like <i>KRAS</i> and <i>TP53</i>. Further, we discuss the potential of epigenetic alterations as diagnostic, prognostic, and predictive biomarkers with an emphasis on their application in liquid biopsies. Finally, we evaluate current and prospective epigenetic therapies, their cooperation with chemotherapy and immunotherapy, and the prospects of new approaches such as CRISPR-based epigenome editing and personalized epigenetic profiling. Together, these findings point to the epigenome as a powerful window of opportunity for understanding, diagnosing, and eventually targeting pancreatic cancer.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1723159"},"PeriodicalIF":0.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121977","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":"Editorial: Epigenetic basis of circadian rhythm and metabolism.","authors":"Rasime Kalkan, Peter S Reinach, Zachary Harvanek, Dongsheng Yan","doi":"10.3389/freae.2025.1736716","DOIUrl":"10.3389/freae.2025.1736716","url":null,"abstract":"","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1736716"},"PeriodicalIF":0.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121940","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 repurposing of carbohydrate metabolic inhibitors for insulin resistance: targeting DNMT1 and HDAC3 for β-cell restoration.","authors":"Muhammad Javid Iqbal, Luis A Salazar","doi":"10.3389/freae.2025.1691949","DOIUrl":"10.3389/freae.2025.1691949","url":null,"abstract":"<p><p>Insulin resistance, a global metabolic crisis affecting a substantial portion of the world's population, involves complex metabolic-epigenetic crosstalk that current therapies fail to address. DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3) progressively silence insulin signaling genes, creating a self-perpetuating cycle of metabolic dysfunction. We present a hypothetical cross-target repurposing strategy leveraging established α-amylase and α-glucosidase inhibitors as potential epigenetic modulators. Through systematic computational screening of 100 natural metabolic enzyme inhibitors against DNMT1 and HDAC3 crystal structures (PBD ID: 3PTA, 4A69), we identified ten dual-target candidates with binding affinities ranging from -8.1 to -10.2 kcal/mol. Kotalanol emerged as the lead compound, demonstrating strong binding to both HDAC3 (-9.8 kcal/mol) and DNMT1 (-10.2 kcal/mol). Molecular docking revealed that polyphenolic metabolic inhibitors share structural features enabling interaction with epigenetic enzyme active sites, particularly zinc-binding motifs and aromatic pockets. ADMET profiling confirmed favorable pharmacokinetic properties for the top candidates. Clinically validated compounds including berberine, curcumin, and EGCG provide proof-of-concept for dual metabolic-epigenetic activity. This repurposing approach offers significant advantages: utilizing compounds with established safety profiles, addressing multiple pathogenic mechanisms simultaneously, and accelerating therapeutic development. By targeting both immediate glucose control and long-term epigenetic preservation, these dual-action compounds could transform diabetes management from symptomatic treatment to mechanistic intervention, potentially reversing insulin resistance progression rather than merely managing hyperglycemia.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1691949"},"PeriodicalIF":0.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121017","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":"Non-coding RNAs at the intersection of epigenetics and cancer metabolism.","authors":"Nicolò Mangraviti, Serena Castelli","doi":"10.3389/freae.2025.1699969","DOIUrl":"10.3389/freae.2025.1699969","url":null,"abstract":"<p><p>Cancer cells are primarily characterized by uncontrolled proliferation, which is closely linked to an increased energy demand. According to this, cancer cells preferentially utilize the glycolytic pathway for energy production. Metabolic regulation in cancer occurs at multiple levels, including post-translational modifications, which are rapid and energy-efficient, as they do not require enzyme degradation. In this context, non-coding RNA-mediated control plays a crucial role, as these small RNAs can directly modulate the mRNAs of key metabolic enzymes or induce epigenetic modulations, ultimately inducing alterations in cancer metabolism. In this mini-review, we summarize how non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), modulate core metabolic pathways, including glycolysis, mitochondrial respiration, lipid metabolism, and amino acid biosynthesis, in cancer. We also highlight recent findings that uncover novel regulatory mechanisms and propose that ncRNAs serve as dynamic integrators of metabolic and oncogenic signals. Understanding these interactions may open new avenues for biomarker identification and ncRNAs-targeted therapies development.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1699969"},"PeriodicalIF":0.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121542","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":"Cancer metabolism rewiring and chromatin methylation: a vulnerable epi-metabolic link.","authors":"Sandra Atlante, Veronica Barbi, Carlo Gaetano, Barbara Illi","doi":"10.3389/freae.2025.1638572","DOIUrl":"10.3389/freae.2025.1638572","url":null,"abstract":"<p><p>Over the past few years, significant advances have been made in understanding the crosstalk between cancer metabolism and gene expression. Whereas higher levels of expression of metabolic enzymes may be considered a conceivable compensatory mechanism to satisfy the increasing request of energy of tumor cells, the detection of changes in the amount and species of intermediate metabolites (oncometabolites) and the discovery of their functional role as co-factors and structural components of chromatin modifiers tightened the link between metabolic shifts and epigenome reshaping in cancer. Changes in the chromatin methylation landscape are one of the epigenetic fingerprints of cancer metabolic rewiring associated with the tumorigenic features of neoplasms. Thus, we propose targeting metabolic enzymes directly involved in cancer methylome remodeling and oncometabolite-dependent chromatin modifiers as innovative tools to reset the epigenome of deregulated cancer cells.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1638572"},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121887","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":"Pioneers of chromosome elimination.","authors":"Luca Comai, Mohan Prem Anand Marimuthu","doi":"10.3389/freae.2025.1648270","DOIUrl":"10.3389/freae.2025.1648270","url":null,"abstract":"<p><p>Epigenetic traits are persistent cellular and organismal properties that do not result from changes in DNA sequence. One such property involves transmission of chromosomes, which entails the formation of highly specialized chromatin structures, the kinetochores, on selected chromosomal regions, called centromeres. Centromere function is essential and centromeres are determined epigenetically by the deposition of a variant histone H3 CENP-A (CENH3 in plants). Either reduced or ectopic function alone leads to genome instability, decreased fitness, aneuploid syndromes, and cancer. At times, however, centromeres malfunction in an apparently programmed mode. This is exemplified by a peculiar centromeric syndrome involving selective elimination of a chromosome set, which can affect a wide range of organisms, including plants. Over half a century ago, plant geneticists described this syndrome in interspecific crosses of barley. Building on their work, we examine the growing understanding of how CENH3 function can be modified to affect epigenetic regulation of centromeres.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1648270"},"PeriodicalIF":0.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121627","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":"Discovery and structural studies of histone demethylases.","authors":"Longfei Peng, Xinze Li, Hao Yang, Haonan Chen, Yue Yang, Shunfeng Peng","doi":"10.3389/freae.2025.1594400","DOIUrl":"10.3389/freae.2025.1594400","url":null,"abstract":"<p><p>The discovery and structural elucidation of histone demethylases represent a groundbreaking advancement in the field of epigenetics. Histone methylation, a critical chromatin modification, was long regarded as irreversible until the identification of histone demethylases overturned this paradigm. In 2004, the discovery of the first histone demethylase, LSD1 (Lysine-Specific Demethylase 1), unveiled the dynamic regulatory mechanisms governing methylation modifications. Subsequent identification of the JmjC domain-containing demethylase family further expanded the diversity and functional repertoire of these enzymes. Structural biology studies have revealed the molecular mechanisms by which these enzymes remove methyl groups via oxidation or hydroxylation reactions, providing key insights into their substrate specificity and catalytic processes. This article will provide a concise overview of the discovery history, fundamental structures, and functional mechanisms of histone demethylases, summarize research progress on identified histone demethylases, and offer novel insights and offer novel insights and suggestions for fundamental research on sites where demethylases remain undiscovered.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1594400"},"PeriodicalIF":0.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121934","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 mechanisms of plasticity and resistance in glioblastoma: therapeutic targets and implications.","authors":"Farzaneh Amirmahani, Saurav Kumar, Sree Deepthi Muthukrishnan","doi":"10.3389/freae.2025.1519449","DOIUrl":"10.3389/freae.2025.1519449","url":null,"abstract":"<p><p>Glioblastoma (GBM), a highly aggressive and malignant form of primary adult brain cancer, poses significant therapeutic challenges. Despite our improved understanding of the cellular and molecular mechanisms underlying tumorigenesis and the evolution of GBM, targeted molecular therapies have failed to improve patient survival outcomes. The failure of standard treatments and targeted therapies is mainly attributed to the acquisition of phenotypic plasticity of tumor cells and GBM stem-like cells. Epigenetic modifications and their mediators have emerged as crucial regulators of phenotypic plasticity, influencing tumor heterogeneity, therapy resistance and disease progression. Here, we summarize and provide insights into epigenetic regulation of GBM plasticity and specifically, focus on the roles played by DNA- and histone modifiers and non-coding RNAs in driving phenotypic plasticity and resistance. We also delve into their dynamics in response to standard therapies and the challenges for targeting them to overcome phenotypic plasticity and resistance in GBM.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1519449"},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149122010","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":"Hansemann's anaplastic theory of cancer after 135 years.","authors":"Steven Henikoff, Kami Ahmad","doi":"10.3389/freae.2025.1607433","DOIUrl":"10.3389/freae.2025.1607433","url":null,"abstract":"<p><p>The term \"anaplasia\" was coined in 1890 to describe chromosomal changes common to primordial cancer cells, but ever since the mechanisms whereby a cell becomes anaplastic has been the subject of much speculation. Recent results based on genomic and epigenomic profiles of cancer patient samples provide a glimpse into early events that lead to aneuploidy, the original defining feature of an anaplastic cell. We propose that the anaplastic cell is one in which RNA Polymerase II hypertranscribes S-phase-dependent histone genes, and the resulting histone excess facilitates DNA replication while competing for CENP-A, causing centromere breaks that initiate whole-arm aneuploidy.</p>","PeriodicalId":101353,"journal":{"name":"Frontiers in epigenetics and epigenomics","volume":"3 ","pages":"1607433"},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121034","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}