Epigenomics最新文献

Background: Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.Q^Ⓡ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.

Methods: We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC₅₀). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.

Results: PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC₅₀. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.

Conclusions: EZH2i plus Carboplatin is a promising combination treatment for AVPC.

Aims: To investigate the biological impact of simultaneous overexpression of lncRNA MEG3 and miR-155, termed a "double hit," on multiple myeloma (MM) cells compared to individual biomarker substitution.

Materials and methods: Human MM cells were transfected with MEG3-overexpressed plasmids and miR-155 mimics. Cell cytotoxicity, apoptosis, and gene expression were evaluated in transfected cells and clinical samples.

Results: MEG3 and miR-155 were significantly downregulated in MM patients, with lower expression levels correlating with advanced disease stages and poorer survival. Dual overexpression induced potent cytotoxic effects in MM cells.

Conclusion: MEG3 and miR-155 are potential tumor suppressors in MM. Simultaneous overexpression of both biomarkers could represent a novel therapeutic strategy, and their levels could serve as diagnostic and prognostic markers.

Aim: The hypoxic tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC) is primarily regulated by hypoxia-inducible factor-1 alpha (HIF-1α), impacting histone acetylation and methylation, which contribute to drug resistance. Vorinostat, a histone deacetylase inhibitor (HDACi), de-stabilizes HIF-1α, while PX-12, a thioredoxin-1 (Trx-1) inhibitor, prevents HIF-1α accumulation. Combining HDACi with a Trx-1 inhibitor may enhance efficacy and reduce resistance by increasing reactive oxygen species (ROS) in cancer cells. This study examines how PX-12 influences vorinostat-induced histone modifications under hypoxia in the OSCC cell line CAL 27 using mass spectrometry.

Materials and methods: The OSCC cell line CAL 27 was used to assess histone post-translational modifications induced by PX-12 and Vorinostat under hypoxic conditions through mass spectrometry.

Results: The proteomic analysis (ProteomeXchange identifier PXD053244) revealed several crucial histone marks, such as H3K4me1, H3K9ac, H3K9me, H3K14ac, H3K27me, H3K36me, H4K12Ac, and H4K16ac. Along with site-specific histone modifications, exposure of cells to vorinostat and PX-12 alone or in combination affects the global acetylation and methylation levels under hypoxia.

Conclusion: Mass spectrometry-based proteomics highlighted the impact of vorinostat and PX-12 on histone acetylation and methylation, offering valuable insights into the epigenetic mechanisms in OSCC and paving a way for epigenetic-based oral cancer therapeutics.

Gliomas, highly aggressive tumors of the central nervous system, present overwhelming challenges due to their heterogeneity and therapeutic resistance. Glioblastoma multiforme (GBM), the most malignant form, underscores this clinical urgency due to dismal prognosis despite aggressive treatment regimens. Recent advances in cancer research revealed signaling pathways and epigenetic mechanisms that intricately govern glioma progression, offering multifaceted targets for therapeutic intervention. This review explores the dynamic interplay between signaling events and epigenetic regulation in the context of glioma, with a particular focus on the crucial roles played by non-coding RNAs (ncRNAs). Through direct and indirect epigenetic targeting, ncRNAs emerge as key regulators shaping the molecular landscape of glioblastoma across its various stages. By dissecting these intricate regulatory networks, novel and patient-tailored therapeutic strategies could be devised to improve patient outcomes with this devastating disease.

The U.S. Developmental Origins of Health and Disease (DOHaD) meeting is an annual conference of primarily U.S. scientists who study early life programming of health and disease. The eighth annual symposium, entitled "Exploring Translational DOHaD Science: From Cells to Communities" was held at the Rizzo Conference Center in Chapel Hill, North Carolina, from October 14 to 16, 2024. The meeting was organized by US-DOHaD President Danielle Christifano and Vice President Kaela Varberg, and other Society Council Members. This year's meeting had record attendance, with 158 attendees from diverse disciplines, and featured 10 keynote speakers, 11 platform talks, and 84 poster presentations. Four major topics were covered: 1) Early nutrition and developmental outcomes, 2) Prenatal origins of child health, 3) Developmental impacts of toxicant exposures, and 4) Metabolic origins of health. Overall, the presented research highlighted the value of studying epigenetic effects of dietary and toxic exposures early in life. Various strategies emerged to address challenges facing the field, such as harnessing the power of nationwide longitudinal birth cohorts, new methods to integrate epigenetic and environmental data across various levels, and the emerging potential of organoids to identify the causal impact of early life exposures.

Aims: Atrioventricular block (AVB) is a prevalent bradyarrhythmia. This study aims to investigate the causal effects of epigenetic aging, as inferred from DNA methylation profiles on the prevalence of AVB by Mendelian randomization (MR) analysis.

Methods: Genetic instruments for epigenetic aging and AVB were obtained from genome-wide association study data in the Edinburgh DataShare and FinnGen biobanks. Univariable and multivariable MR analyses were conducted to evaluate causal associations. Additionally, we employed sensitivity tests to assess the robustness of the MR findings.

Results: MR analysis showed that genetically predicted GrimAge acceleration was significantly associated with a higher risk of AVB (inverse variance-weighted: p = 0.010, 95% confidence interval (CI) = 1.024-1.196; weighted median: p = 0.031, 95% CI = 1.009-1.215). However, no evidence supported a causal relationship between AVB and epigenetic aging. The association between epigenetic aging and AVB was established using multivariate MR analysis after adjusting for various risk factors. Sensitivity analyses confirmed the reliability and robustness of the results.

Conclusion: Our findings suggest that epigenetic aging in GrimAge may increase the risk of AVB, emphasizing the importance of addressing epigenetic aging in strategies for AVB prevention.

Aim: We aim to assess association of DNA methylation (DNAm) at birth with total immunoglobulin E (IgE) trajectories from birth to late adolescence and whether such association is ethnicity-specific.

Methods: We examined the association of total IgE trajectories from birth to late adolescence with DNAm at birth in two independent birth cohorts, the Isle of wight birth cohort (IOWBC) in UK (n = 796; White) and the maternal and infant cohort study (MICS) in Taiwan (n = 60; Asian). Biological pathways and methylation quantitative trait loci (methQTL) for associated Cytosine-phosphate-Guanine sites were studied.

Results: Two total IgE trajectories, high vs. low, were inferred from each of the two cohorts. Associations of DNAm at 103 CpGs with IgE trajectories in IOWBC and at 476 CpGs in MICS were identified. Between the two cohorts, of the identified CpGs, one was in common, methQTL site cg16711274 (mapped to gene MINAR1), and 17 pathways were common with at least four linked to airway diseases.

Conclusion: The findings suggest at-birth epigenetics may explain ethnicity differences in total IgE trajectories later in life.

Suicide continues to be a significant public health issue globally, claiming over 700,000 lives annually. It is, therefore, important to assess the suicide risk properly and provide intervention in a timely fashion. While the heritability of suicidal behavior is around 50%, it does not explain the factors involved in causality. Recent evidence suggests that gene x environment interaction plays a vital role in suicidal behavior. In this paper, we critically evaluate the association between adolescent suicidal behavior and epigenetic modifications, including DNA methylation, histone modification, and non-coding RNAs, as well as epigenetic-based treatment options. It was noted that the prevalence of suicidal behavior in adolescents varied by age and sex and the presence of psychiatric disorders. Childhood adversity was closely associated with suicidal behavior. Studies show that alterations in epigenetic modifications may increase the risk of suicidal behavior independent of mental illnesses. Because epigenetic factors are reversible, environmental enrichment or the use of pharmacological agents that can target specific epigenetic modulation may be able to reduce suicidal behavior in this population.

Over the past century, human lifespan has increased remarkably, yet the inevitability of aging persists. The disparity between biological age, which reflects pathological deterioration and disease, and chronological age, indicative of normal aging, has driven prior research focused on identifying mechanisms that could inform interventions to reverse excessive age-related deterioration and reduce morbidity and mortality. DNA methylation has emerged as an important predictor of age, leading to the development of epigenetic clocks that quantify the extent of pathological deterioration beyond what is typically expected for a given age. Machine learning technologies offer promising avenues to enhance our understanding of the biological mechanisms governing aging by further elucidating the gap between biological and chronological ages. This perspective article examines current algorithmic approaches to epigenetic clocks, explores the use of machine learning for age estimation from DNA methylation, and discusses how refining the interpretation of ML methods and tailoring their inferences for specific patient populations and cell types can amplify the utility of these technologies in age prediction. By harnessing insights from machine learning, we are well-positioned to effectively adapt, customize and personalize interventions aimed at aging.