Clinical Epigenetics最新文献

Background: While DNA methylation profiling from peripheral blood mononuclear cells (PBMCs) has demonstrated utility in cancer risk prediction, notably for non-small cell lung cancer (NSCLC), its prognostic value for survival stratification in Chinese lung adenocarcinoma (LUAD) patients remains unestablished. This study addresses whether PBMC-derived methylation signatures can discriminate clinical outcomes in EGFR-mutation LUAD subgroups.

Methods: We performed genome-wide methylation analysis of PBMCs from LUAD patients using the Infinium Methylation EPIC 850 K array. Clinical characteristics were associated with overall survival (OS) through Cox regression. Prognostic differentially methylated positions (DMPs) were identified via Lasso regression, followed by the construction of risk-score models. Functional enrichment (KEGG/GO) and tissue microarray-based immunohistochemistry (IHC) for FKBP4 expression (n = 90 LUAD samples) were conducted. Analyses were conducted in R 4.4.1 with curated Bioconductor packages.

Results: In the retrospective cohort of 174 Chinese LUAD patients (April 2014-September 2019), PBMC analysis of 128 cases revealed 12 hypomethylated DMPs were associated with OS. EGFR-mutant patients (n = 66) showed 325 significant DMPs (|Δβ|≥ 0.06, P ≤ 0.01), with four DMPs (cg05802998, cg19313959, cg00685115, cg15224444) independently predicting OS. The cg19313959 located in the TSS1500 region of FKBP4 gene (Δβ = 0.21) demonstrated the strongest methylation shift. Reduced FKBP4 protein expression was associated with improved survival (HR = 0.42, 95%CI 0.24-0.72). In EGFR-wildtype patients (n = 51), three prognostic DMPs emerged from 2,531 candidates. EGFR mutation-specific prognostic scoring models were established successfully, while pathway analyses revealed divergent biological processes between EGFR subgroups.

Conclusion: In this epigenome-wide study based on PBMCs in Chinese patients with LUAD, methylation signatures dependent on EGFR mutations and predictive of survival were identified.

Background: Idiopathic dilated cardiomyopathy (iDCM) is a multifactorial disease with a complex pathogenesis involving diverse molecular mechanisms. Among these, epigenetic mechanisms, including both DNA methylation and microRNAs (miRNAs)-mediated regulation, play an important role in determining the disease phenotype. However, the interplay between the DNA methylome and the miRNA transcriptome in iDCM remains largely unexplored.

Methods: We conducted a cross-cohort multiomic integrative analysis of left ventricular (LV) tissue samples from iDCM patients and control (CNT) donors. DNA methylation profiling was performed using the Infinium MethylationEPIC BeadChip, whereas ncRNA-seq was used to assess transcriptomic changes.

Results: We identified a subset of three miRNAs exhibiting both differential methylation in their promoter regions and differential expression in their primary and mature forms. Notably, the miRNA hsa-miR-433-3p (r = 0.671, p < 0.01), which is involved in fibrotic pathways, appear to be significantly correlated with the left ventricular ejection fraction (LVEF), an established echocardiographic marker of cardiac function.

Conclusions: This study enhances our understanding of the epigenetic mechanisms shaping the miRNA transcriptomic landscape in iDCM, suggesting potential roles for these miRNAs in cardiac dysfunction and myocardial fibrosis.

Background: Epidemiological studies have shown a small but significantly increased risk of leukemia in children conceived by in vitro fertilization. Atypical DNA methylation patterns observed in pediatric cancers are suspected to occur in utero, and it is known that periconceptional conditions linked to assisted reproductive technologies (ART) are responsible for DNA methylation modifications.

Results: Using databases and systematic literature screens, we derived a list of cancer/leukemia genes (n = 1246 and n = 532 genes, respectively, corresponding to 1466 individual genes) and of differentially methylated genes (DMG) in leukemia (n = 2642) and pre-leukemia (n = 381). These lists were cross-referenced with DMG (n = 93) curated from 18 ART Epigenome-Wide Association Studies (EWAS) (2369 samples). Among the ART DMG, more than one-third (n = 33) were leukemia, and six were pre-leukemia DMG, all representing a significant enrichment. Seven of the enriched genes (NTM, PRSS16, SCAND3, SYCP1, TP73, ZNF184, and ISL1-DT) showed concordant methylation between ART and leukemia/pre-leukemia. Moreover, five of the ART DMG are known targets for somatic/germline alterations in leukemia: ATP10A, CHD2, FBRSL1, FGFR2, and SORCS1. The ART DMG were not significantly enriched in cancer genes, supporting the hypothesis that ART may not link broadly to any cancer type but rather to leukemia.

Conclusion: This study indicates that relatively few genes that are known targets for somatic/germline mutation in cancer experience DNA methylation changes in individuals conceived through ART. By contrast, DNA methylation disturbances reported in leukemia represent more than one-third of those associated with ART conception, thus raising the question of their role in leukemia risk in ART-conceived individuals. Among them, a few critical genes such as TP73, a tumor suppressor, were shown to be targeted for hypermethylation, both in ART and leukemia, warranting further investigation.

Background: Exposure to air pollution is known to contribute to the development and exacerbation of asthma symptoms, impacting respiratory health through complex, not yet fully understood biological mechanisms. It is hypothesized that DNA methylation (DNAm) changes triggered by air pollutants may mediate these effects on asthma symptom control.

Objectives: We aimed to investigate the effects of air pollution on DNAm in peripheral blood and asthma control. We also explored whether DNAm could potentially mediate the relationship between air pollution exposure and asthma control.

Methods: This study included 651 participants with asthma exposed to ambient air pollutants, NO₂, PM_2.5, PM₁₀, O₃, elemental carbon (EC), and NOx. Self-reported Asthma Control Test (ACT) scores for the preceding six-month period were used to assess asthma symptom control. DNAm was quantified using the Infinium HumanMethylation450 BeadChip array in whole blood and CD4 + naive T cells. An Epigenome-Wide Association Study (EWAS) was conducted to identify CpGs associated with air pollutants, with sample sizes ranging from 169 to 329. The Causal Inference Test (CIT) was employed to examine whether DNAm mediates the effects of air pollution exposure on asthma control.

Results: Exposure to short-term PM₁₀ was associated with poorer asthma control. We identified DNA methylation changes linked to air pollution in both whole blood and CD4 + cells, with associations observed for PM₁₀, EC and NOx in whole blood, and for PM₁₀, NO₂ and PM_2.5 in CD4 + cells. Three CpG sites in whole blood-cg04605532 (p = 0.0004), cg05492904 (p = 0.0008), and cg23622322 (p = 0.001)- and one CpG in CD4 + cells -cg10022248 (p = 0.0084)-were associated with air pollution exposure and linked to asthma control. Additionally, CIT-based mediation analysis identified two CpG sites, cg02324789 (p = 0.05) and cg10758278 (p = 0.06), as potential mediators in the relationship between short-term exposure to PM₁₀ and asthma control.

Discussion: These findings suggest that air pollution-associated changes in DNA methylation may affect asthma control for some loci, thus help elucidate underlying mechanisms in asthmatic patients. These epigenetic alterations highlight potential targets for understanding the pathophysiology of asthma due to air pollution. While our findings suggest possible links between air pollution, DNA methylation, and asthma control, more evidence is needed to establish causal relationships and unravel the complexities of these connections.

As a member of the hemoglobin family, γ-globin is usually persistently expressed at high levels to perform the oxygen-carrying function during fetal development. In recent years, related gene editing clinical trials have confirmed that reactivation of γ-globin expression is a promising therapeutic strategy for treating β-hemoglobinopathies, including β-thalassemia and sickle cell disease. Human γ-globin expression is finely regulated by multiple mechanisms, and a deeper understanding of the mechanisms will help develop drugs that target its activation. With the advancement of biotechnology, epigenetic modifications (EMs) and protein post-translational modifications (PPTMs) have shown irreplaceable roles in the regulation of γ-globin expression. Therefore, this review will comprehensively summarize the regulatory mechanisms of EMs and PPTMs on γ-globin to provide new ideas for the treatment of β-hemoglobinopathies.

Background: The trace elements (TEs) selenium, zinc, copper, manganese, iodine and iron are essential micronutrients that support essential metabolic functions. Imbalance in their homeostasis might contribute to the pathogenesis of major age-related chronic diseases including type 2 diabetes (T2D) and cardiovascular diseases (CVD). Emerging evidence suggests that TEs may affect health outcomes via epigenetic changes. However, few epigenome-wide association studies (EWAS) have explored TE-associated DNA methylation markers and their links to chronic disease outcomes.

Methods: We conducted TE-specific exploratory EWAS using a random subcohort (n = 1030) from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. The association between identified CpG sites and incident chronic diseases was evaluated using a case-cohort design comprising random subcohort participants and incident cases of T2D (n = 654) and CVD (n = 334). DNA methylation was measured with the MethylationEPIC BeadChip array. We used Prentice-weighted Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of TE-associated CpG sites with each incident chronic disease.

Results: In the copper EWAS, we identified six CpG sites (cg00398673, cg03957124, cg05736499, cg07573872, cg11503550, and cg18513344) that were significantly associated with serum copper concentrations with a False Discovery Rate < 0.05. All associated CpG sites showed lower methylation levels in association with higher serum copper levels. Higher methylation levels of cg00398673 (HR per SD: 0.74, 95% CI 0.63-0.88), cg03957124 (HR per SD: 0.52, 95% CI 0.41-0.66), cg05736499 (HR Q5 vs Q1: 0.25, 95% CI 0.14-0.47), and cg18513344 (HR Q5 vs Q1: 0.37, 95% CI 0.24-0.57) were associated with decreased risk of developing T2D, and higher methylation levels of cg07573872 were associated with decreased risk of developing CVD (HR per SD: 0.85, 95% CI 0.72-0.99). We did not observe any CpG sites that were significantly associated with other TEs.

Conclusions: Serum copper levels are inversely associated with a number of CpG sites. Methylation levels at these CpG sites were inversely associated with developing T2D and CVD. These findings may provide new insights on understanding the increased risk of T2D and CVD with elevated blood copper levels.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially the only curative option for high-risk acute myeloid leukemia (AML) patients. However, disease relapse remains the principal cause of treatment failure of these patients, and outcomes of salvage treatments are poor. This research seeks to evaluate the efficacy and safety of a dual epigenetic targeting maintenance therapy with chidamide and azacitidine (AZA) in patients with high-risk AML post-allo-HSCT.

Methods: This multicenter, open-label, phase 2 prospective clinical trial (ChiCTR2300067593) recruited and followed up 48 patients diagnosed with high-risk AML post-allo-HSCT from 3 hospitals in China from November 2021 to March 2024. Chidamide (5 mg) was administered orally once daily for 5 days, combined with AZA (75 mg/m²) subcutaneously daily for 5 days, respectively. Treatment started as early as 3 months after transplantation. All patients were in complete remission before each maintenance cycle. A total of 6 cycles was recommended.

Results: The 2-year cumulative incidence of relapse (CIR) was 8.4% (95% CI 4.4-12.4%), 2-year relapse-free survival (RFS) was 91.6% (95% CI 87.6-95.6%), and overall survival (OS) was 97.9% (95% CI 95.8-100%). At the end of the follow-up period, 4 patients relapsed, of which 1 patient died of leukemia recurrence; the other three patients underwent second allo-HSCT and are still alive in remission. The most common adverse events (AEs) were hematological toxicity. No grade > 3 AEs were noted. Graft-versus-host disease (GVHD) occurred in 29.2% (14/48) of patients. Six cases (6/48, 12.5%) were complicated with infection. No treatment-related mortality occurred.

Conclusions: Dual epigenetic targeting maintenance treatment with CHI-AZA has an acceptable toxicity profile and might potentially be effective to prevent relapse in high-risk AML patients after allo-HSCT.

Trial registration: ClinicalTrials.gov, ChiCTR2300067593. Registered January 12, 2013.

DNA methylation is an epigenetic modification that regulates gene expression by adding methyl groups to DNA, affecting cellular function and disease development. Machine learning, a subset of artificial intelligence, analyzes large datasets to identify patterns and make predictions. Over the past two decades, advances in bioinformatics technologies for arrays and sequencing have generated vast amounts of data, leading to the widespread adoption of machine learning methods for analyzing complex biological information for medical problems. This review explores recent advancements in DNA methylation studies that leverage emerging machine learning techniques for more precise, comprehensive, and rapid patient diagnostics based on DNA methylation markers. We present a general workflow for researchers, from clinical research questions to result interpretation and monitoring. Additionally, we showcase successful examples in diagnosing cancer, neurodevelopmental disorders, and multifactorial diseases. Some of these studies have led to the development of diagnostic platforms that have entered the global healthcare market, highlighting the promising future of this field.

Acquired therapy resistance is a dynamic process associated with early epigenetic modifications reshaping gene transcription across multiple cellular pathways, ultimately giving rise to drug-tolerant persister (DTP) cells. Unraveling the mechanisms that sustain DTP cell survival and drive their evolution into stable drug-resistant cells (DRC) is crucial for developing targeted therapies. Cisplatin-tolerant and cisplatin-resistant models were established using liver and gastric cancer cell lines for the first time to explore these mechanisms. Our investigation centered on the distinct epigenetic landscapes of DTP and DRC cells following cisplatin exposure. RNA sequencing revealed that DTP cells exhibit downregulation of pathways involved in cell cycle regulation, DNA replication, transcription, and chromatin maintenance while upregulating those associated with cell-cell communication and cytokine signaling. Interestingly, these transcriptional changes revert in the DRC state, suggesting a high degree of plasticity during the DTP phase. Furthermore, DTP cells have elevated levels of heterochromatin markers, H3K9me3, H3K27me3, and HP1α, along with their methyltransferases, G9a and Ezh2. Knockdown studies and inhibition of the enzyme activity of these modifiers showed suppression of DTP cell emergence. Valproic acid (VPA), a phase III candidate, was further assessed in vivo, where its sequential administration with cisplatin significantly reduced tumor burden versus cisplatin alone. These findings highlight the therapeutic promise of targeting epigenetic modifications to pre-sensitize cancer cells to chemotherapy, thereby restricting the survival advantage of DTP cells.