SEARCH · Search PubMed

Results for “hypomethylation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2025

Integrating advanced analytical methods to assess epigenetic marks affecting response to hypomethylating agents in higher risk myelodysplastic syndrome.

BACKGROUND: Patients with higher-risk (HR) myelodysplastic syndrome (MDS), ineligible for allogeneic hematopoietic stem cell transplantation (alloHSCT), require prompt therapeutic interventions, such as treatment with hypomethylating agents (HMAs) to restore normal DNA methylation patterns, mainly of oncosuppressor genes, and consequently to delay disease progression and increase overall survival (OS). However, response assessment to HMA treatment relies on conventional methods with limited capacity to uncover a wide spectrum of underlying molecular events. METHODS: We implemented liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess 5' methyl-2' deoxycytidine (5mdC), 5' hydroxy-methyl-2'-deoxycytidine (5hmdC) levels and global adenosine/thymidine ([dA]/[T]) ratio in bone marrow aspirates from twenty-one HR MDS patients, pre- and post-HMA treatment. Additionally, targeted methylation analysis was performed by interpretation of NGS-methylation (MeD-seq) data obtained from the same patient cohort. RESULTS: LC/MS-MS analysis revealed a significant hypomethylation status in responders (Rs), already established at baseline and a trend for further DNA methylation reduction post-HMA treatment. Non-responders (NRs) reached statistical significance for DNA hypomethylation only post-HMA treatment. The 5hmdC epigenetic mark was approximately detected at 37.5-40% among NRs and Rs, implying the impairment of the natural active demethylation pathway, mediated by the ten-eleven (TET) 5mdC dioxygenases. R and NR subgroups displayed a [dA]/[T] ratio < 1 (0.727 - 0.633), supporting high frequences of 5mdC transition to thymidine. Response to treatment, according to whole genome MeD-seq data analysis, was associated with specific, scattered hypomethylated DMRs, rather than presenting a global effect across genome. MeD-seq analysis identified divergent epigenetic effects along chromosomes 7, 9, 12, 16, 18, 21, 22, X and Y. Within statistically significant selected chromosomal bins, genes encoding for proteins and non-coding RNAs with reversed methylation profiles between Rs and NRs, were highlighted. CONCLUSIONS: Implementation of powerful analytical tools to identify the dynamic DNA methylation changes in HR MDS patients undergoing HMA therapy demonstrated that LC-MS/MS exerts high efficiency as a broad-based but rapid and cost-effective methodology (compared to MeD-seq) to decode different perspectives of the epigenetic background of HR MDS patients and possess discriminative efficacy of the response phenotype to HMA treatment.

Humans↗

PubMed2011

Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation.

Alterations in nucleoli, including increased numbers, increased size, altered architecture and increased function are hallmarks of prostate cancer cells. The mechanisms that result in increased nucleolar size, number and function in prostate cancer have not been fully elucidated. The nucleolus is formed around repeats of a transcriptional unit encoding a 45S ribosomal RNA (rRNA) precursor that is then processed to yield the mature 18S, 5.8S and 28S RNA species. Although it has been generally accepted that tumor cells overexpress rRNA species, this has not been examined in clinical prostate cancer. We find that indeed levels of the 45S rRNA, 28S, 18S and 5.8S are overexpressed in the majority of human primary prostate cancer specimens as compared with matched benign tissues. One mechanism that can alter nucleolar function and structure in cancer cells is hypomethylation of CpG dinucleotides of the upstream rDNA promoter region. However, this mechanism has not been examined in prostate cancer. To determine whether rRNA overexpression could be explained by hypomethylation of these CpG sites, we also evaluated the DNA methylation status of the rDNA promoter in prostate cancer cell lines and the clinical specimens. Bisulfite sequencing of genomic DNA revealed two roughly equal populations of loci in cell lines consisting of those that contained densely methylated deoxycytidine residues within CpGs and those that were largely unmethylated. All clinical specimens also contained two populations with no marked changes in methylation of this region in cancer as compared with normal. We recently reported that MYC can regulate rRNA levels in human prostate cancer; here we show that MYC mRNA levels are correlated with 45S, 18S and 5.8S rRNA levels. Further, as a surrogate for nucleolar size and number, we examined the expression of fibrillarin, which did not correlate with rRNA levels. We conclude that rRNA levels are increased in human prostate cancer, but that hypomethylation of the rDNA promoter does not explain this increase, nor does hypomethylation explain alterations in nucleolar number and structure in prostate cancer cells. Rather, rRNA levels and nucleolar size and number relate more closely to MYC overexpression.

Adult↗

PubMed2026

DNA hypomethylation of the OLFM1 gene in patients with depression.

OBJECTIVE: Depression is a heterogeneous psychiatric disorder and a growing public health concern, characterized by its high prevalence, recurrence rate, and association with suicide. There is evidence suggesting that both genetic susceptibility and environmental factors can regulate gene expression through DNA methylation, thereby influencing the occurrence and development of depression. The olfactory sensory neuropeptide 1 (OLFM1) protein is a risk factor for mental disorders. However, there are no reports yet regarding the correlation between the OLFM1 gene and depression, nor have there been any studies on the association between OLFM1 gene DNA methylation and depression. METHODS: Genomic DNA was extracted from peripheral blood samples of patients with depression (n = 100) and healthy controls (n = 100) using the QIAamp DNA Blood Mini Kit. Subsequently, the extracted genomic DNA was subjected to bisulfite treatment using the EZ DNA Methylation-Gold™ kit. DNA methylation levels of 107 CpG sites in six fragments of OLFM1 exon 1 and its downstream were detected by the Illumina HiSeq platform using MethylTarget™ technology. RESULTS: Methylation levels across the overall OLFM1 CpG island and its six fragments (OLFM1-1 to OLFM1-6) were significantly reduced in the depression group relative to controls. Analysis of the OLFM1 gene fragments revealed that 84 of 107 CpG sites were significantly hypomethylated in depressed individuals. When patients were divided by sex, male patients displayed hypomethylation at 65 CpG sites, substantially more than the 37 sites found in females. CONCLUSION: OLFM1 hypomethylation is associated with depression and may serve as a potential epigenetic biomarker.

Humans↗

PubMed2026

ADCY2 promoter hypomethylation in adolescents with borderline personality disorder: An RRBS study with targeted BSP replication.

BACKGROUND: Borderline Personality Disorder (BPD) is characterized by emotional dysregulation, impulsivity, and interpersonal instability. Although genetic and environmental contributions to BPD have been investigated, epigenetic correlates in adolescents remain poorly understood. The cyclic adenosine monophosphate (cAMP) signaling pathway is implicated in stress responsivity and emotion regulation, but its epigenetic variation in adolescent BPD remains understudied. METHODS: DNA methylation profiling was performed using Reduced Representation Bisulfite Sequencing (RRBS) in buccal epithelial DNA from adolescents with BPD (n = 15) and healthy controls (HC; n = 15). Differentially methylated regions (DMRs) were identified using metilene, a computational tool for detecting DMRs from bisulfite sequencing data, and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Associations between methylation signals and borderline personality features were examined. Adenylate cyclase 2 (ADCY2) promoter methylation was examined using targeted bisulfite sequencing PCR (BSP) in an independent cohort (BPD n = 5; HC n = 5). RESULTS: RRBS identified 7641 DMRs between BPD and HC, with enrichment in pathways related to neuronal signaling and synaptic organization. A hypomethylated DMR was detected in the ADCY2 promoter, a gene implicated in cAMP signaling. Lower ADCY2 promoter methylation was associated with greater clinical severity, including emotional dysregulation, borderline traits, anxiety symptoms, and self-injury behaviors (r=-0.71 to -0.83; all p < 0.0001). Hypomethylation of the ADCY2 promoter was replicated in the independent cohort. CONCLUSIONS: This exploratory two-stage epigenetic study suggests that ADCY2 promoter hypomethylation in peripheral buccal epithelial DNA is associated with core symptom dimensions of adolescent BPD. These findings support a role for cAMP-related epigenetic variation in BPD and warrant replication in longitudinal studies.

ADCY2↗

PubMed2024

Sulfonamide-induced DNA hypomethylation disturbed sugar metabolism in rice (Oryza sativa L.).

DNA methylation is well-accepted as a bridge to unravel the complex interplay between genome and environmental exposures, and its alteration regulated the cellular metabolic responses towards pollutants. However, the mechanism underlying site-specific aberrant DNA methylation and metabolic disorders under pollutant stresses remained elusive. Herein, the multilevel omics interferences of sulfonamides (i.e., sulfadiazine and sulfamerazine), a group of antibiotics pervasive in farmland soils, towards rice in 14 days of 1 mg/L hydroponic exposure were systematically evaluated. Metabolome and transcriptome analyses showed that 57.1-71.4 % of mono- and disaccharides were accumulated, and the differentially expressed genes were involved in the promotion of sugar hydrolysis, as well as the detoxification of sulfonamides. Most differentially methylated regions (DMRs) were hypomethylated ones (accounting for 87-95 %), and 92 % of which were located in the CHH context (H = A, C, or T base). KEGG enrichment analysis revealed that CHH-DMRs in the promoter regions were enriched in sugar metabolism. To reveal the significant hypomethylation of CHH, multi-spectroscopic and thermodynamic approaches, combined with molecular simulation were conducted to investigate the molecular interaction between sulfonamides and DNA in different sequence contexts, and the result demonstrated that sulfonamides would insert into the minor grooves of DNA, and exhibited a stronger affinity with the CHH contexts of DNA compared to CG or CHG contexts. Computational modeling of DNA 3D structures further confirmed that the binding led to a pitch increase of 0.1 Å and a 3.8° decrease in the twist angle of DNA in the CHH context. This specific interaction and the downregulation of methyltransferase CMT2 (log2FC = -4.04) inhibited the DNA methylation. These results indicated that DNA methylation-based assessment was useful for metabolic toxicity prediction and health risk assessment.

DNA Methylation↗

PubMed2025

ANXA3 hypomethylation as a prognostic biomarker in hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a poor prognosis. This research aimed to characterize the expression pattern and clinical value of Annexin A3 (ANXA3) in HBV-ACLF patients. METHODS: First of all, ACLF-related datasets were downloaded from the Gene Expression Omnibus (GEO) database to carry out bioinformatics analyses. RT-qPCR, ELISA, and Methylight were used to measure ANXA3 gene expression and promoter methylation levels. A validation cohort was leveraged to further validate the results. RESULTS: Transcriptome analysis showed that ANXA3 was among the most differentially expressed genes when comparing dead patients with HBV-ACLF to those with survivors. The mRNA and serum levels of ANXA3 were elevated, and methylation levels were decreased in HBV-ACLF patients. The PMR value of ANXA3 in patients with HBV-ACLF was negatively correlated with inflammation-related cytokines IL-6, TNF-α, and IL-1β, as well as quantitative clinical parameters AST, TBIL, PT, INR, NEUT%, and MELD score, and positively correlated with PTA (all p < 0.05). In HBV-ACLF patients, ANXA3 was considered to be an independent influence factor for the 90-day mortality. It was also found that ANXA3, especially hypomethylation, was associated with 28- and 90-day overall survival in patients with HBV-ACLF based on receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and Kaplan-Meier curves. CONCLUSIONS: ANXA3 hypomethylation has a prominent predictive value for short-term mortality in patients with HBV-ACLF and may serve as a promising biomarker of HBV-ACLF prognosis.

Humans↗

PubMed2025

DNA methylation and multi-omics profiling of T cells uncovers chemotactic pathways and proliferation-linked hypomethylation in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a loss of orexin-producing cells in the brain and involves autoimmune mechanisms, including the presence of autoreactive T cells. In this study, we performed genome-wide DNA methylation analysis using both CD4+/CD8+ T cells from 42 NT1 patients and 42 controls across discovery and replication cohorts. To identify methylation changes more robustly associated with the disease, we prioritized differentially methylated regions (DMRs) over single-site differentially methylated positions (DMPs). Furthermore, to validate and interpret DMP-level associations, we integrated genome-wide genotype and gene expression data obtained from the same individuals. As a result, the DMR analysis identified 15 reproducible DMRs in CD4+ T cells and 5 in CD8+ T cells, with most DMRs shared between the two cell types. Shared DMRs included regions associated with CCL5 (p = 2.1E-02) and CCR4 (p = 8.3E-03). Integrative analysis with genotype and gene expression data also showed that the DMP related to S100A4, which promotes lymphocyte migration through CCR5 and CXCR3 receptors, was associated with the disease in CD4+ T cells. Pathway analysis of genes identified through both the DMR and integrative analyses indicated enrichment in cell chemotaxis-related pathways, suggesting that aberrant chemokine-mediated cell migration plays a central role in NT1 pathogenesis. Further, NT1-associated methylation changes were predominantly hypomethylation events, significantly enriched in non-promoter, non-CpG island regions (p = 1.74E-102). We further observed that global hypomethylation levels were correlated with hypoSC, a mitotic index estimated from methylation data, highlighting increased T cell proliferation in NT1.

Humans↗

PubMed1977

Correlation between hypomethylation of DNA and expression of globin genes in Friend erythroleukemia cells.

This report identifies L-ethionine as an inducer of differentiation in murine erythroleukemia cells. When Friend erythroleukemia cells are grown in the presence of 4mM L-ethionine, globin mRNA accumulates and in 4-5 days, 25-30% of the cells in the culture contain hemoglobin. Incubation of the cells with bromodeoxyuridine prevents both ethionine-induced accumulation of globin mRNA and erythroide differentiation. At the concentration where L-ethionine acts as an inducer of FL cell differentiation it inhibits methylation of DNA and tRNA in vivo but does not prevent macromolecular synthesis or cell division. To establish whether a link existed between inhibition of a specific methyltransferase and activation of globin synthesis in FL cells, we examined the degree of hypomethylation of DNA and tRNA from FL cells induced to differentiate with dimethylsulfoxide and butyrate. In contrast to the tRNA from ethionine-treated cells, tRNA from cells induced by butyrate or Me2SO cannot be methylated in vitro using homologous enzymes. DNA isolated from cells exposed to any of the three inducers, however, was significantly hypomethylated when compared with DNA from uninduced cells. These data suggest that methylation of DNA may play a role in the regulation of gene expression.

Cell Differentiation↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2025

Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.

Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.

Humans↗

PubMed2026

ICAM-1 Hypomethylation Predicts Poor Prognosis in Patients With Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a high short-term mortality rate. Therefore, early and accurate prognostic prediction is crucial for precise clinical management. This study aims to investigate the expression patterns of intercellular adhesion molecule-1 (ICAM-1) and its predictive value for the short-term prognosis of patients with HBV-ACLF. The Methylight method was used to quantitatively detect ICAM-1 promoter methylation level in peripheral blood mononuclear cells (PMBCs) of 286 participants. Meanwhile, the mRNA and plasma expression levels of ICAM-1 were determined using RT-qPCR and ELISA, respectively. The ICAM-1 promoter methylation levels in PBMCs of HBV-ACLF patients were significantly lower than those in chronic hepatitis B (CHB) patients and healthy controls (HCs), whereas the mRNA and plasma expression levels of ICAM-1 were markedly elevated. The ICAM-1 methylation levels in HBV-ACLF patients correlated with specific clinical parameters. Among HBV-ACLF patients, ICAM-1 methylation levels were significantly lower in the non-survivor groups at both 28 and 90 days. The study further revealed that ICAM-1 methylation level serves as an independent influencing factor for the prognosis of HBV-ACLF patients at 28 and 90 days. Based on ROC curve and Kaplan-Meier curves, ICAM-1 methylation levels demonstrated excellent performance in predicting 28- and 90-day mortality in patients with HBV-ACLF. In conclusion, patients with HBV-ACLF exhibit hypomethylation of the ICAM-1 promoter. The combination of ICAM-1 promoter methylation level and MELD score can effectively enhance the predictive ability for the short-term prognosis of HBV-ACLF patients.

Humans↗

PubMed2026

Telomere-to-telomere genome of Phoebe chekiangensis reveals that age-dependent CHG hypomethylation promotes floral transition via MADS-box gene activation.

Phoebe species are renowned for their highly valuable 'golden thread' timber; however, their protracted juvenile phase presents a significant obstacle to mechanistic investigations of floral induction. Phoebe chekiangensis, a rare early-flowering representative within this genus, provides a unique model system for dissecting the vegetative-to-reproductive phase transition. Nevertheless, the absence of a high-quality reference genome has severely hindered molecular insights into its developmental regulation. Here, we present the first telomere-to-telomere (T2T) genome assembly for P. chekiangensis, comprising two completely gap-free haplotypes with contig N50 values exceeding 65 Mb, base-level quality scores >36, and Long Terminal Repeat Assembly Index scores surpassing the gold standard threshold of 20. Approximately 29 000 genes were annotated per haplotype, supported by a BUSCO completeness score of >97%. Age-resolved transcriptomic landscapes identified two MADS-box transcription factors, PcMADS5 (AP1-like) and PcMADS19.1 (SOC1-like), as core activators of the floral transition. Both genes triggered precocious flowering when ectopically expressed in Arabidopsis thaliana. Whole-genome bisulfite sequencing revealed a progressive, age-dependent decline in CHG (where H is A, C, or T) DNA methylation, which was particularly pronounced at the PcMADS19.1 locus. Notably, DML1/2, which mediate active DNA demethylation, were coordinately upregulated during the onset of reproductive growth. Chemical demethylation using 5-azacytidine further diminished CHG methylation and selectively enhanced PcMADS19.1 expression, confirming a causal relationship between CHG hypomethylation and transcriptional activation. This work delivers the first chromosome-scale T2T genome within the genus Phoebe and uncovers CHG demethylation as a previously unrecognized epigenetic switch governing reproductive competence in woody perennials.

Journal Article↗

PubMed2026

Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model.

PURPOSE: As risk stratification for patients with AML treated with lower-intensity venetoclax-based therapy remains suboptimal, we developed and validated a prognostic model integrating clinical, cytogenetic, and molecular features. METHODS: We assembled a multinational data set comprising 2,092 adults with newly diagnosed AML treated with hypomethylating agents plus venetoclax (HMA + VEN). One thousand nine hundred eighteen patients with complete data were randomly divided into training (70%) and internal validation (30%) cohorts. Two independent external validation cohorts were assembled (n = 500 and n = 222). Modeling overall survival (OS), Elastic Net regression was applied in 1,000 bootstrap samples from the training cohort to select variables for a Ridge regression, which generated a continuous Prognostic Risk Integration for Survival Modeling (PRISM) score and risk categories based on tertiles (PRISM-3: low, moderate, high). These PRISM indices were then computed for the validation cohorts and compared with the 4-gene classifier (based on mutations in FLT3-ITD, N/KRAS, and TP53). RESULTS: PRISM integrated 17 clinical and genomic variables and demonstrated a linear association with OS. PRISM-3 stratified survival consistently across all cohorts (median OS: 25.1-28.8 months for low risk, 12.5-14.7 months for moderate risk, and 5.8-6.7 months for high risk; P < .001). Compared with the 4-gene classifier, PRISM-3 reassigned approximately 40% of patients (and >50% of those with favorable risk) and demonstrated significantly better discrimination in validation cohorts (C-index 0.63-0.65 v 0.59-0.61; P < .05). CONCLUSION: PRISM is a validated prognostic model for patients with AML receiving HMA + VEN that improves survival risk stratification beyond current standard tools and supports individualized, risk-adapted clinical decision making. The model, the PRISM-AML Risk Calculator, is publicly available.

Humans↗

PubMed2026

DNA methylation as a driver of lung fibroblast senescence in COPD.

Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of CDKN1A, CDKN2A, and CDKN2B was higher, while LMNB1 expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes CDKN1A (9), CDKN2A (1), and LMNB1 (9). Among these, seven CpG sites (4 for CDKN1A and 3 for LMNB1) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes CDKN1A and LMNB1.NEW & NOTEWORTHY This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators CDKN1A and LMNB1. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.

Humans↗

PubMed2026

A Comparative Analysis of the Methylation Status of Non-Coding RNA Promoters in Fibroid and Matched Myometrium.

Uterine fibroids exhibit dysregulated expression of non-coding RNAs (ncRNAs), although the underlying mechanisms remain incompletely understood. We investigated promoter DNA methylation and its relationship with ncRNA expression in fibroids. Genomic DNA from eight paired fibroid and matched myometrial tissues was analyzed using MeDIP-chip to identify differentially methylated ncRNA promoters. Selected candidates were validated by methylation-specific PCR (MSP) in 16 paired samples, and transcript expression was assessed by qRT-PCR in 68-94 paired specimens. MeDIP-chip identified 538 lncRNAs and 61 miRNAs with differential promoter methylation, including 300 hypermethylated and 238 hypomethylated lncRNAs and 47 hypermethylated and 14 hypomethylated miRNAs. Promoter methylation was not significantly correlated with transcript expression (r = -0.1224). MSP confirmed hypermethylation of LINC-PINT and MIR9-3 and hypomethylation of WT1-AS and TTLL10-AS1. Correspondingly, LINC-PINT and MIR9-3 expression was decreased, whereas WT1-AS and TTLL10-AS1 expression was increased in fibroids. However, LINC-PINT and TTLL10-AS1 methylation did not fully correspond with MeDIP-chip findings. These results reveal widespread ncRNA promoter methylation alterations in uterine fibroids but demonstrate that genome-wide methylation does not consistently predict transcript expression, highlighting the complexity of ncRNA epigenetic regulation and the importance of locus-specific validation.

Humans↗

PubMed2026

CDC20B Dysregulation: Links to Tumor Prognosis and Immunity.

OBJECTIVE: This study aimed to clarify the pan-cancer expression pattern, upstream regulatory mechanisms, prognostic relevance, and immune associations of CDC20B. METHOD: Using public databases (GTEx, GEO, and TCGA), we examined CDC20B expression and its associations with prognosis and tumor immunity across multiple cancers. Immunohistochemistry (IHC) on an independent clinical cohort was performed to validate CDC20B upregulation in tumor tissues. Promoter methylation, genetic alterations, and immune infiltration were analyzed using bioinformatics tools (cBioPortal, UALCAN, TIMER2.0, ESTIMATE). Functional enrichment was assessed by GSEA and single-cell state analysis (CancerSEA). RESULTS: CDC20B was markedly upregulated in most tumor types (p < 0.001), with strong diagnostic efficiency (AUC > 0.7 in 15 cancers) and potential regulation by promoter hypomethylation. IHC confirmed its overexpression in clinical tumor tissues. However, the prognostic impact of CDC20B was cancer-type-specific: high expression correlated with poor overall survival in UCS, LGG, KIRC, and OV, but with favorable survival in BRCA, LUAD, and PAAD. CDC20B expression was associated with immune infiltration patterns, showing negative correlations with ImmuneScore in most cancers but positive correlations with CD8+ T cells in PAAD. Functional analyses indicated involvement in EMT, KRAS/NF-κB signaling, and DNA damage response pathways. DISCUSSION: The dual prognostic role of CDC20B suggests context-dependent functions, likely influenced by tumor microenvironment composition and underlying oncogenic programs. Promoter hypomethylation emerges as a potential epigenetic driver of overexpression. The associations with immune modulation and genomic instability suggest that CDC20B is a candidate biomarker, though causal relationships require experimental validation. CONCLUSION: CDC20B may contribute to tumor progression in a context-dependent manner, with its prognostic impact varying across cancer types. Its role in tumor immunity and oncogenic pathways warrants further investigation, particularly in stratified patient populations.

CDC20B↗

PubMed2025

Prenatal organophosphate ester exposure and epigenetic changes at birth: a characterization of the methylome in the ECHO cohort.

BACKGROUND: Prenatal exposure to organophosphate esters (OPEs) affects multiple child health domains. Alterations to the DNA methylome are a plausible mechanism through which these changes occur. This study characterized DNA methylation signatures at birth associated with prenatal OPE biomarkers. METHODS: We included 736 mother-infant pairs from 7 sites in the Environmental influences on Child Health Outcomes (ECHO) Cohort. Five OPE biomarkers were quantified in maternal urine samples collected during the second and third trimesters and modeled as log2-transformed continuous variables. Using covariate-adjusted linear regression, we tested associations between OPE biomarkers and locus-specific, regional, and global cord blood DNA methylation changes measured by Illumina 450 K and EPIC arrays, and gestational epigenetic age measured by the Knight gestational age epigenetic clock generated with measures from the 27 K, 450 K, and EPIC arrays. When feasible, we examined relationships by sex. FINDINGS: Global hypomethylation at multiple regions was associated with BDCPP concentrations (p = 0.003 to 0.02, coef = -0.002). Differentially methylated regions annotated to PCDHGB1 and SLC43A2 were associated with BDCPP and DPHP concentrations, respectively (FDR q < 0.05). In sex-specific analyses, global hypomethylation was associated with prenatal BDCPP (p = 0.006 to 0.03, coef = -0.0003 to -0.0002) and DBUP_DIBP (p = 0.01, coef = -0.0007 to -0.0006) concentrations in females; and global hypermethylation was associated with DBUP_DIBP concentrations in males (p < 0.05, coef = 0.0004). BCETP concentrations were significantly associated with decelerated epigenetic aging at birth in females (p < 0.05, coef = -0.05). INTERPRETATION: Prenatal exposure to OPEs impacts child methylation at birth, suggesting a potential mechanism for the association between prenatal OPE exposure and child health outcomes.

Humans↗

PubMed2025

LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer.

Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.

Male↗