Epigenetics最新文献

{"title":"Decoding chromatin-associated RNA (caRNA) interaction networks: from genome-wide dynamic capture to epigenetic mechanisms in plants and animals.","authors":"Can Liu, Wenze Li, Qi Lv, Rui Su","doi":"10.1080/15592294.2026.2733375","DOIUrl":"10.1080/15592294.2026.2733375","url":null,"abstract":"<p><p>Chromatin-associated RNAs (caRNAs) serve as central hubs for regulation within the cell nucleus and are involved in key biological processes such as transcriptional homeostasis, chromatin remodeling, and transgenerational inheritance. In recent years, the development of various genome-wide RNA-chromatin interaction capture technologies has made it possible to resolve the spatial interaction networks between caRNAs and chromatin with high precision. This paper systematically reviews the concepts, functions, and interaction patterns of caRNA, and provides a comprehensive overview of the principles, characteristics, technical biases, and applicable scenarios in the fields of targeted and non-targeted identification technologies. Building on this foundation, this paper conducts a comparative analysis of caRNA regulatory mechanisms in animals and plants across four functional dimensions: the organization of three-dimensional chromatin topology, RNA modification-mediated epigenetic regulatory switches, the transmission of environmental and transgenerational signals, and the pathological mechanisms associated with caRNA network dysregulation. Through this comparative analysis, this paper reveals the common characteristics of caRNA-mediated functional regulation in animals and plants, as well as lineage-specific adaptive strategies, and discusses the challenges and future directions in this field regarding single-cell resolution, AI-assisted data analysis, and translational applications.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2733375"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cell type enrichment analysis tool for brain DNA methylation data (CEAM).","authors":"Joshua Müller, Valentin T Laroche, Jennifer Imm, Luke Weymouth, Joshua Harvey, Rick A Reijnders, Adam R Smith, Daniel van den Hove, Katie Lunnon, Rachel Cavill, Ehsan Pishva","doi":"10.1080/15592294.2025.2604360","DOIUrl":"10.1080/15592294.2025.2604360","url":null,"abstract":"<p><p>DNA methylation (DNAm) signatures are highly cell type-specific, yet most epigenome-wide association studies (EWAS) are performed on bulk tissue, potentially obscuring critical cell type-specific patterns. Existing computational tools for detecting cell type-specific DNAm changes are often limited by the accuracy of cell type deconvolution algorithms. Here, we introduce CEAM (Cell-type Enrichment Analysis for Methylation), a robust and interpretable framework for cell type enrichment analysis in DNA methylation data. CEAM applies over-representation analysis with cell type-specific CpG panels from Illumina EPIC arrays derived from nuclei-sorted cortical post-mortem brains from neurologically healthy aged individuals. The constructed CpG panels were systematically evaluated using both simulated datasets and published EWAS results from Alzheimer's disease, Lewy body disease, and multiple sclerosis. CEAM demonstrated resilience to shifts in cell type composition, a common confounder in EWAS, and remained robust across a wide range of differentially methylated positions, when upstream modeling of cell type composition was modeled with sufficient accuracy. Application to existing EWAS findings generated in neurodegenerative diseases revealed enrichment patterns concordant with established disease biology, confirming CEAM's biological relevance. The workflow is publicly available as an interactive Shiny app (https://um-dementia-systems-biology.shinyapps.io/CEAM/) enabling rapid, interpretable analysis of cell type-specific DNAm changes from bulk EWAS.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2604360"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p53-mediated epigenetic regulation in the pathogenesis of endometriosis.","authors":"Jiameng Wang, Qi Liao, Xiaoling Feng","doi":"10.1080/15592294.2026.2705611","DOIUrl":"10.1080/15592294.2026.2705611","url":null,"abstract":"<p><p>Endometriosis (EMs) is a common gynecological disorder affecting reproductive‑aged women, characterized by ectopic endometrial growth and chronic pelvic pain that severely impairs quality of life. Although its pathogenesis remains incompletely understood, accumulating evidence indicates that the tumor suppressor p53 and aberrant epigenetic modifications play critical roles in EMs initiation and progression. p53 expression is significantly reduced in ectopic lesions, leading to apoptosis resistance and hyperproliferation of endometrial cells. Importantly, p53 dysfunction contributes to EMs through at least four epigenetic mechanisms: (1) p53 transcriptionally represses DNA methyltransferases (DNMTs), and its loss indirectly promotes locus‑specific hypermethylation and silencing of tumor suppressors; (2) p53, via its interaction with histone modifiers, influences their recruitment to target genes, and p53 impairment synergizes with histone deacetylase dysregulation to create a pro‑proliferative, anti‑apoptotic microenvironment; (3) p53 functionally interacts with the chromatin remodeler ARID1A, and their co‑dysruption impairs chromatin accessibility and immune homeostasis; (4) p53 coordinates non‑coding RNA networks (e.g. lncRNA MALAT1, miR‑34a) that regulate epithelial-mesenchymal transition, angiogenesis, and apoptosis. This review systematically summarizes the p53‑mediated epigenetic regulatory network in EMs and highlights potential therapeutic opportunities targeting p53-epigenetic crosstalk. Future studies should investigate synergistic mechanisms among different epigenetic layers and validate these findings in multi‑center clinical cohorts.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2705611"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential methylation at novel putative imprinting control regions on chromosome 20 associated with childhood obesity.","authors":"Catherine F Everly, Terrence K Allen, David A Skaar, Bruce A Corliss, Dereje D Jima, Rachel L Maguire, Halah Jadallah, Randy L Jirtle, Susan K Murphy, Jung-Ying Tzeng, Cathrine Hoyo","doi":"10.1080/15592294.2026.2732477","DOIUrl":"10.1080/15592294.2026.2732477","url":null,"abstract":"<p><p>DNA methylation may link early-life exposures to later obesity risk; however, most studies examine individual CpG sites using commercial arrays that cover < 5% of the genome and often overlook biologically relevant regulatory regions. Imprinting control regions (ICRs) regulate parent-of-origin gene expression and are enriched for growth and metabolic genes, representing strong candidates for developmental programming of obesity. In 586 participants of the Newborn Epigenetics STudy (NEST), we leveraged the novel Human Imprintome Array to measure methylation at >1,000 characterized and putative ICRs genome-wide in umbilical cord blood. We applied principal component and kernel machine regression to identify ICR methylation at birth associated with sustained childhood obesity, defined as BMI ≥ 95th percentile during most of childhood. Sustained childhood obesity was associated with differential methylation at seven ICRs in cord blood, with 2-10% mean differences between obesity and normal weight groups, including novel regions localized to chromosome 20q11.1-20q11.21 (ICR_1182, ICR_1179, ICR_1181, ICR_1177, ICR_1180, and ICR_1165), mapping to or near <i>CDC27P4, LINC01597, DUX4L37</i>, and <i>DUX4L34</i>, and ICR_927 mapping to previously characterized <i>ZNF597/NAA60</i>. Most ICRs overlapped multiple transcriptional regulator binding sites. Associations persisted in peripheral blood collected in later childhood at ages 8-16 years. Among offspring of mothers with pre-pregnancy obesity, an additional 50 associations were identified. Sex-stratified analyses revealed no further insights. These findings identify novel ICRs - particularly on chromosome 20q - as potential early-life epigenetic biomarkers of childhood obesity. If replicated, these stable ICR methylation patterns may identify children at risk for obesity at birth, informing targeted prevention before obesity develops and guiding novel therapeutic strategies.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2732477"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse patterns of transcriptional regulation and epigenetic reprogramming within PMDs contribute to ESCC progression by regulating EMT and immunosuppression.","authors":"Yan Huang, Jing Xue, Xue Luan, Huixia Zhang, Jingke Ding, Jintao Xu, Zhongjun Zhao, Quanda Li, Kunkun Tu, Xinyu Wang, Wenjie Ge","doi":"10.1080/15592294.2026.2745292","DOIUrl":"https://doi.org/10.1080/15592294.2026.2745292","url":null,"abstract":"<p><p>Partially methylated domains (PMDs) represent extensive genome-wide hypomethylated regions that drive genomic instability and proto-oncogene activation. However, their complex regulatory influence on tumor-specific transcriptional networks remains largely elusive. In this study, we developed a robust computational pipeline to characterize aberrant PMD landscapes across pan-cancer. We specifically focused on the epigenetic features associated with transcriptional dysregulation in esophageal squamous cell carcinoma (ESCC). By analyzing gene expression patterns, we classified PMDs into four distinct classes and revealed that several immunosuppressive genes were recurrently activated within Tumor-PMDs across various cancers. While these PMDs were generally marked by elevated repressive H3K27me3 and diminished active histone modifications, the activated genes within them paradoxically exhibited a precise, localized enrichment of H3K9ac and H3K27ac near their transcription start sites (TSSs). This localized epigenetic rewiring suggests a potential correlation where collaborative histone modification landscapes may shape oncogenic chromatin remodeling to license transcriptional dysregulation. Furthermore, we identified a robust co-expression axis between the prognostic gene <i>ATP6V0D2</i> and established immune checkpoints (<i>HAVCR2</i>, <i>TDO2</i>). Elevated <i>ATP6V0D2</i> expression was found to potentially contribute to ESCC progression and poor prognosis by activating the complement system and epithelial-mesenchymal transition (EMT) pathways. Capitalizing on these findings, virtual screening and <i>in vitro</i> validation suggested that caffeic acid could act as a potential ATP6V0D2-binding compound, effectively suppressing the migration and viability of ESCC cells. This study further nominates caffeic acid as a candidate compound for further mechanistic and therapeutic investigation in ESCC.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2745292"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential CpG methylation in the <i>Interferon Gamma</i> (<i>IFNG</i>) promoter correlates with viral load and transcriptional control in people with HIV.","authors":"Megha S Srivatsa, Momtahina Tahmida, Tara Tenenbaum, Susan J Little, Brian LaMere, Sara Gianella, Sarah A LaMere","doi":"10.1080/15592294.2026.2693337","DOIUrl":"10.1080/15592294.2026.2693337","url":null,"abstract":"<p><p>HIV persistence is facilitated by immune evasion strategies that reshape host immune responses. As the <i>Interferon Gamma</i> (<i>IFNG</i>) gene encodes a key immunoregulatory cytokine whose transcriptional competence is governed by promoter CpG methylation, we hypothesized that HIV plasma RNA would track with epigenetic remodeling at the <i>IFNG</i> promoter, altering IFNG mRNA transcription. DNA methylation at the <i>IFNG</i> promoter was quantified by bisulfite sequencing in PBMCs from people with HIV (PWH) with high (<i>n</i> = 16; >5000 copies/µL), medium (<i>n</i> = 18; 500 to 4999 copies/µL), or undetectable (<i>n</i> = 18; ≤50 copies/µL) plasma HIV RNA. Corresponding IFNG mRNA was quantified by RT-qPCR, with a sensitivity analysis adjusting for T cell abundance. High detectable plasma HIV RNA was associated with significant <i>IFNG</i> hypomethylation across 4 out of 5 CpG sites in the <i>IFNG</i> promoter compared to those with medium HIV RNA, while those with undetectable plasma HIV RNA showed no significant differences after adjusting for duration of infection. Accordingly, IFNG mRNA transcription was significantly elevated in participants with high plasma HIV RNA compared to medium (<i>p</i> = 0.037), which strengthened after modeling TCF7 expression as a covariate to account for varying T cell counts (<i>p</i> = 0.02). These findings provide the first <i>in vivo</i> evidence correlating HIV viral load with epigenetic transcriptional control of <i>IFNG</i> in peripheral blood.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2693337"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13327351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine modification of mRNAs in retinal ischemia-reperfusion in mice.","authors":"Jingying Liang, Yuke Li, Yuwen Wen, Zhidong Li, Caibin Deng, Yehong Zhuo, Yangyang Li, Yingting Zhu","doi":"10.1080/15592294.2026.2700836","DOIUrl":"10.1080/15592294.2026.2700836","url":null,"abstract":"<p><p>Retinal ischemia-reperfusion injury (RIR) is the main pathogenic mechanisms of acute glaucoma, diabetic retinopathy, central retinal vein occlusion. As a common post-transcriptional modification of eukaryotic RNAs, N6-methyladenosine (m⁶A) is associated with the pathogenesis of different diseases, including angiogenesis, through the regulation of RNA metabolism and functions. The aim of this study was to identify the potential relevance of m⁶A RNA methylation in pathogenesis of RIR. A total of 10,851 mRNAs and 23,270 associated m⁶A methylation modified peaks were identified in the RIR group. Similarly, 10,391 mRNAs and 22,935 associated m⁶A methylation modified peaks were detected in the Sham group. MeRIP-seq identified 3,871 RIR-specific m⁶A peaks and 3,624 Sham-specific m⁶A peaks, in addition to 19,399 shared peaks between groups. Gene ontology (GO) analysis showed that hypermethylated mRNAs were enriched in cellular process, cellular anatomical entity, and binding, while hypomethylated mRNAs were enriched in synaptic signaling, synapse, and gated channel activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that hypermethylated mRNAs were involved in tight junction, hippo signaling pathway, and PI3K-Akt signaling pathway, while hypomethylated mRNAs were involved in Neuroactive ligand-receptor interaction, glutamatergic synapses, cholinergic synapses. Joint analysis identified mRNAs with differential m⁶A methylation and expression simultaneously. Among them, the expression patterns of <i>Irx4</i>, <i>Kdr</i>, and <i>Lyz2</i> were confirmed by RT-qPCR to be consistent with the sequencing results. The results revealed an altered m⁶A epitranscriptome in RIR retinas. These methylated RNAs may act as novel modulators and targets in RIR.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2700836"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct and indirect genetic effects of birthweight predisposition on child DNA methylation at birth.","authors":"Nicole Creasey, Leonard Frach, Elena Isaevska, Janine F Felix, Charlotte Cecil, Jean-Baptiste Pingault, Alexander Neumann","doi":"10.1080/15592294.2026.2654101","DOIUrl":"10.1080/15592294.2026.2654101","url":null,"abstract":"<p><p>Birthweight is heritable and strongly associated with epigenetic differences at birth. It is unclear whether a genetic birthweight score is associated with DNA methylation (DNAm) and, if so, whether through direct genetic effects (i.e. child genotype) or indirect genetic effects (i.e. parental genotype, independent of child genotype), which are suspected to be mediated by the prenatal environment (e.g. metabolic factors). We constructed polygenic scores (PGS) for birthweight predisposition in mothers and children using an existing 'pre-adjusted' GWAS assessing maternal indirect effects (maternal genotype on offspring birthweight, correcting for offspring genotype) or fetal effects (offspring genotype on offspring birthweight, correcting for maternal genotype) in 2116 families from the Generation R Study. Offspring DNAm levels at 829 birthweight-related sites were then regressed on both maternal and fetal effect PGS. Additionally, we aggregated 829 DNAm sites into a methylation profile score for birthweight (MPS-BW) and tested which pregnancy health factors (<i>n</i> = 13) might mediate genetic effects. We identified six DNAm sites associated with maternal indirect effects and the birthweight MPS revealed indirect genetic associations, as well. Paternal genotype was not associated with offspring DNAm in this study but was limited by lower sample size and lack of GWAS on paternal indirect effects, thus requiring a posteriori disentanglement of direct and indirect effects. Gestational age partly mediated maternal indirect effects on DNAm, but no other mediators were identified. Results did not depend on offspring sex. This study presents first evidence of maternal genetic effects on offspring birthweight being associated with offspring epigenetic patterns at birth.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2654101"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Culture-dependent decoupling of <i>H19</i> allele-specific expression from <i>H19/IGF2</i>:IG-DMR methylation in experimental models.","authors":"Céline Selenou, Frédéric Brioude, Laure Sudre, Aurélie Pham, Irène Netchine, Marie-Laure Sobrier, Éloïse Giabicani","doi":"10.1080/15592294.2026.2690360","DOIUrl":"10.1080/15592294.2026.2690360","url":null,"abstract":"<p><p>Genomic imprinting is an epigenetic mechanism leading to the monoallelic expression of a subset of genes, mainly regulated by DNA methylation at imprinting control regions (ICRs). Silver-Russell syndrome (SRS) is a paradigmatic imprinting disorder in which loss of methylation at the 11p15.5 <i>H19/IGF2</i>:IG-DMR is associated with downregulation of <i>IGF2</i> and biallelic expression of <i>H19</i>. Currently, the allele-specific expression of imprinted genes is widely inferred from ICR methylation without direct assessment. Here, we quantified <i>H19</i> allele-specific expression together with <i>H19/IGF2</i>:IG-DMR methylation in control (<i>n</i> = 32) and SRS (<i>n</i> = 12) samples spanning tissues and commonly used cellular models, including fibroblasts, induced pluripotent stem cells (iPSCs) and dental pulp stem cells (DPSCs). Overall, <i>H19</i> allele-specific expression was concordant with <i>H19/IGF2</i>:IG-DMR methylation in tissues, iPSCs and fibroblasts, with clear allelic bias in controls and predominantly biallelic expression in SRS samples. Nevertheless, some SRS-derived fibroblast lines retained an allelic bias despite loss of methylation. In addition, a subset of control DPSCs with balanced methylation exhibited biallelic <i>H19</i> expression. We showed that the observed decoupling between methylation and allele-specific expression was associated with culture-related procedures, including repeated passaging and freeze-thaw cycles in DPSCs. These findings show that ICR methylation does not always faithfully reflect imprinted gene expression and therefore cannot be uncritically used as a proxy for imprinting. They further indicate that culture-related procedures can promote loss of imprinting and support the systematic combined assessment of ICR DNA methylation and allele-specific expression when establishing cellular models for imprinting disorders.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2690360"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation signatures of sporadic colorectal cancer with microsatellite instability.","authors":"Rebecca Ward, Molly Endicott, Bethan Mallabar-Rimmer, Joe Burrage, Kitty Sherwood, Qiwen Huang, Joseph C Ward, Steve Thorn, Connor Woolley, Sophie J Wood, Emma Dempster, Harry D Green, Ian Tomlinson, Amy P Webster","doi":"10.1080/15592294.2026.2711191","DOIUrl":"10.1080/15592294.2026.2711191","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a heterogeneous disease shaped by genetic and epigenetic alterations. Approximately 20% of CRCs exhibit widespread CpG island hypermethylation, termed the CpG Island Methylator Phenotype (CIMP), frequently accompanied by <i>MLH1</i> promoter hypermethylation, deficient mismatch repair (dMMR) and microsatellite instability (MSI). However, methylation patterns associated with MSI, independent of CIMP and <i>MLH1</i> silencing, and the influence of anatomical location and patient age on the CRC methylome remain incompletely defined. We performed epigenome-wide DNA methylation profiling of 259 sporadic CRCs using the Illumina EPICv2 array. Differential methylation between MSI and microsatellite stable (MSS) CRCs was assessed after adjustment for tumour purity and anatomical location, then <i>MLH1</i> promoter methylation and CIMP status, to delineate MSI-associated methylation changes. Additionally, we evaluated the effects of anatomical location and age on methylation patterns. While differential methylation between MSS and MSI CRCs was dominated by <i>MLH1</i> promoter hypermethylation, additional adjustment for <i>MLH1</i> hypermethylation and CIMP identified 656 CpG sites associated with MSI, beyond the global methylator phenotype. These included hypermethylation at <i>LRP6</i>, <i>GSK3β</i>, and <i>CDK12</i>, identifying differential methylation of genes involved in WNT signalling and transcriptional regulation. Within MSI CRCs, we observed the co-occurrence of <i>MLH1</i> hypermethylation with promoter hypermethylation at <i>TXNRD1</i>. Anatomical location was strongly associated with methylation, whereas age had more modest effects. These results identify methylation changes associated with sporadic MSI beyond CIMP status and <i>MLH1</i> hypermethylation, reveal heterogeneity within MSI CRCs, and indicate that anatomical location is a major determinant of the CRC methylome, advancing molecular stratification of CRC.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"21 1","pages":"2711191"},"PeriodicalIF":3.7,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}