Epigenomics最新文献

Aim: Non-small cell lung cancer (NSCLC) has caused a heavy social and economic burden worldwide. DNA methylation, as an emerging blood biomarker, has great potential for early detection of NSCLC.

Methods: Seven CpG sites of the S100P gene were detected quantitatively using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry in 845 NSCLC patients (91.4% at stage I) and 1007 controls. Logistic regression was used to calculate covariate-adjusted ORs and 95% CIs.

Results: The logistic regression-based quartile analysis (Q1 lowest vs. Q4 highest) disclosed the association between hypomethylation of six CpG sites in the S100P gene and NSCLC (ORs ranged from 1.51 to 2.32, p and p for trend ≤0.004 for all), and even in NSCLC at stage I (ORs ranged from 1.53 to 2.26, p and p for trend ≤0.004 for all). The subgroup analyses suggested enhanced association in male gender and older age. Additionally, decreased methylation of S100P_CpG_5 was markedly relevant with advanced tumor size and tumor stage (p = 0.003 and p = 0.007, respectively).

Conclusions: Using quantitative mass spectrometry, we investigated an association between S100P hypomethylation in peripheral blood and NSCLC and suggested the great potential of DNA methylation signatures in whole blood for early detection of NSCLC.

Leishmaniasis is a complex immuno-metabolic infectious disease regulated by epigenetic mechanisms in both the parasite and host. Epigenetic modifications such as chromatin remodeling, histone post-translational modifications (PTMs), and non-coding RNAs (ncRNAs) modulate gene expression to promote parasite survival and alter host immune responses. This review highlights species-specific epigenetic changes across Leishmania species contributing to pathogenesis and explains how the parasite manipulates host immune signaling through epigenetic pathways, including co-infection and co-morbidity models. Host factors like nuclear factor of activated T cells 5 (NFAT5) and Src homology 2 domain-containing phosphatase-1 (SHP-1), along with parasite-derived proteins such as Su(var)3-9, enhancer of zeste [E(z)], trithorax (SET) proteins, and histones, are emerging as promising epigenetic therapeutic targets. Furthermore, histone PTMs and transcription factors are critical epigenetic modifications supporting parasite survival. Synthetic gene circuits can modulate host and parasite epigenomes. Synthetic biology enables the assembly of genetic parts and pools to engineer cells with novel biological functions. A structured literature review using Web of Science, PubMed, and Scopus was performed, using keywords like epigenetics of Leishmania, epigenetics alterations in host with leishmaniasis, Leishmania and comorbidity and disease-specific terms. This review underscores the future potential of epigenetics and synthetic biology-based strategies in controlling leishmaniasis.

Aims: Matrix metalloproteinases (MMPs) promote prostate cancer (PCa) progression by degrading the extracellular matrix and enhancing metastasis. PCa is considered an "epigenetic catastrophe" due to disrupted histone modifications caused by chromatin-modifying enzyme dysregulation. We previously showed that lysine demethylase 6A (KDM6A) and 6B (KDM6B) are higher in metastatic PCa (LNCaP) versus benign prostatic hyperplasia (BPH-1). We investigated whether their elevation contributes to MMP upregulation.

Methods and results: LNCaP cells were treated with the KDM6 inhibitor GSK-J4, and mRNA levels of 23 MMPs were quantified by RT-qPCR. GSK-J4 reduced mRNA levels of 6 MMPs (MMP-7, -8, -11, -15, -16, and -19) out of 23. Decline in pre-spliced mRNA levels of MMP-7, -11, and -16 by GSK-J4 suggested transcriptional changes; only MMP-11 and -16 exhibited corresponding protein decreases. Among downregulated MMPs, MMP-7, -11, -15 and -16 mRNA were higher in LNCaP versus BPH-1, confirmed at protein level for MMP-11 and -16. KDM6A - but not KDM6B - siRNA reduced MMP-11 and -16 expression. GSK-J4 increased histone3 lysine27 trimethylation (H3K27me₃) enrichment at MMP-11 and -16 promoters, as shown by Chromatin Immunoprecipitation (ChIP).

Conclusion: KDM6A demethylates H3K27me₃ at MMP-11 and -16 promoters, sustaining their enhanced expression in PCa and revealing a novel epigenetic mechanism driving metastasis-associated protease expression.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), affects an estimated 6.8 million individuals worldwide. Although biological or small molecule drug therapies can improve patient outcomes, loss of response to treatment over time remains high, highlighting the need for new precision medicine strategies. Dysbiosis of the gut microbiome is characterized by the loss of beneficial microbes and an overgrowth of pro-inflammatory pathobionts. In IBD, gut dysbiosis contributes to chronic intestinal inflammation via altered metabolite profiles and epithelial barrier disruption. Recent advancements in multi-omics integration offer approaches to better understand the pathogenesis of IBD. Epigenomic studies have revealed disease-specific DNA methylation and enhancer activation patterns that reshape immune pathways and compromise epithelial barrier integrity, key mechanisms in IBD pathophysiology. These molecular signatures allow for the stratification of IBD patients into distinct subgroups, allowing for more targeted therapeutic strategies. Here we explore the potential benefits of integrating gut microbiome and both host transcriptomics and epigenomics to improve disease management in IBD patients. While challenges remain - such as data standardization, computational complexity, and cost - the progression of multi-omics methodologies is expected to improve patient outcomes by reducing high treatment failure rates in IBD patients.

Introduction: Titanium dioxide nanoparticles (TiO₂NPs) are relevant nanomaterials (NMs) for biomedicine and industry, which raise concerns about its effects on human health, particularly through ingestion. Several studies found that exposure to NMs can lead to DNA methylation changes. DNA methylation regulates gene expression, playing a vital role in development and disease, with aberrant methylation linked to cancer and other health conditions.

Aim: We aimed at identifying DNA methylation changes in intestinal cells exposed to three TiO₂NPs (NM-102, NM-103, NM-105), either digested or undigested. Their cellular effects were investigated by functional pathway and gene ontology (GO) analysis.

Results: 48, 41, 55 differentially methylated genes (DMG) were identified after exposure to undigested NM-102, NM-103, NM-105; 71, 65, 55 DMG in the digested counterparts. Undigested TiO₂NPs affected many G-proteins/adenylate cyclase-related pathways (PKA, glucagon, GPER1, CREB1, ADORA2B); the digested had lower impact. Cancer-related pathways were shared. Enriched molecular functions were mainly transcription-related; different biological processes were enriched if TiO₂NPs were digested or not.

Conclusions: TiO₂NPs exposure causes DNA methylation changes that have a functional impact on intestinal cells, which differs with its physicochemical properties and digestion. NM-105 caused hypermethylation, unlike the other TiO₂NPs. This study highlights DNA methylation relevance in assessing NMs' toxicity.

Aim: The Histone methyl transferase KMT5C/SUV4-20H2 has been described as a promising marker in several types of cancer. We investigated the impact of KMT5C knockdown on cell proliferation capacity as well as its association with clinic pathological features in HNSC patients.

Methods: The relative level of KMT5C was measured by quantitative real-time PCR in HNSC lineages with high and low levels of SET/I2PP2A protein, and the cell proliferation capacity was evaluated after the knockdown of KMT5C. Furthermore, statistical tests were used to verify the association of KMT5C levels and pathological features in HNSC patients.

Results: The knockdown of KMT5C decreased the levels of H4K20me2 and miR-137 while upregulating SET/I2PP2A, KI67, p-Rb, and PCNA proteins. The cell proliferation capacity of the HNSC lineage was also increased after the knockdown of KMT5C. Furthermore, the higher KMT5C level is associated with better survival, while a lower KMT5C level is associated with perineural invasion in HNSC patients.

Conclusion: KMT5C levels regulate targets involved in cell proliferation and represent a potential biomarker for predicting survival and perineural invasion in HNSC.

Aim: To investigate the role of SUV39H2 in glioblastoma (GBM) stem cells (GSCs) and assess whether co-targeting SUV39H2 and SUV39H1 more effectively disrupts GSC maintenance, offering a potential strategy to improve GBM treatment.

Methods: Single-cell RNA-seq was used to assess SUV39H2 expression in GSCs. GSC growth and stemness were evaluated using tumorsphere formation assay and extreme limiting dilution assay. Gene expression at the mRNA and protein levels was measured by RT-qPCR and western blot, respectively. Publicly available datasets were analyzed to investigate SUV39H2 expression patterns and its clinical prognostic significance in GBM and glioma.

Results: SUV39H2 is overexpressed in GSCs relative to non-stem GBM cells. Its depletion impairs GSC proliferation and stemness. Co-targeting SUV39H2 and SUV39H1 enhances GSC disruption. High SUV39H2 expression correlates with poor glioma prognosis.

Conclusion: SUV39H2 is a novel regulator of GSC maintenance. Dual targeting of SUV39H2 and SUV39H1 May offer a potential therapeutic approach for GBM.

Background: Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk remains understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship.

Research design and methods: Using data from the 2016 Health and Retirement Study (n = 3,346, age >50), we estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and cognitive status, classified using the Langa-Weir method. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell-type proportions.

Results: Cognitive impairment prevalence was 16%. A doubling of IL-6 was associated with a 12% higher odds of cognitive impairment (OR = 1.12, 95% CI: 1.02-1.22), and 0.77 years of GrimAge acceleration (95% CI: 0.64-0.90). Similar associations were found for CRP and IGF-1. Mediation analysis indicated that 17.7% (95% CI: 7.0-50.9%) of the IL-6-cognitive impairment association was mediated by the GrimAge acceleration. Comparable mediated estimates were found for CRP and IGF-1.

Conclusions: Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.

RNA modifications represent a pivotal epitranscriptomic layer modulating gene expression beyond the classic central dogma. Increasing studies have revealed their essential roles in orchestrating mammalian development and contributing to congenital disorders. In this review, we focus on seven well-characterized RNA modifications, including N⁶-methyladenosine(m⁶A), N¹-methyladenosine(m¹A), 5-methylcytosine (m⁵C), N⁴-acetylcytosine (ac⁴C), N⁷-methylguanosine (m⁷G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing, and briefly introduce emerging marks like N¹-methylguanosine at position 9 (m¹G9) and N²-methylguanosine (m²G). We first summarize their distribution patterns and regulatory mechanisms. Then, we examine their stage-specific functions during early embryogenesis, from fertilization to post-implantation. Further, we integrate current evidence linking RNA modifications to craniofacial development, categorized into system-associated and localized craniofacial malformations. Special attention is given to their crosstalk with chromatin dynamics and neural crest cell plasticity. Finally, we discuss their potential as environmental sensors and therapeutic targets, emphasizing the need to decode their roles in craniofacial morphogenesis. Understanding the mechanistic roles of RNA modifications in craniofacial morphogenesis opens new avenues for uncovering disease etiology, discovering diagnostic biomarkers, and designing targeted therapies. A structured literature review using PubMed and Web of Science was performed, using keywords like RNA modifications, craniofacial malformations and epitranscriptomics.

Nutrition during pregnancy can influence fetal development and health across the lifespan. Prenatal nutrition is mechanistically linked to the epigenetic landscape because nutrients supply methyl groups and regulate microRNAs and proteins involved in epigenetic modifications. This review focuses on the epigenomic landscape in both the umbilical cord blood, as a window into fetal development, and in the placenta, as the master regulator of fetal nutrition. We highlight associations between the epigenome and nutrients found in prenatal multiple micronutrient supplements, including one carbon metabolism nutrients, antioxidant vitamins, vitamin D, trace minerals, and omega-3 polyunsaturated fatty acids. We discuss challenges in this field including reliance on observational studies, non-linear relationships, cell type-specific effects, and sex-specific effects. We also highlight emerging approaches to explore the role of nutritional epigenomics in development including critical windows of exposure and novel epigenetic and epitranscriptomic features by applying new technological advancements. A better understanding of how nutrients affect the epigenomic landscape in early life can inform further mechanistic studies and improve clinical guidance surrounding nutrient and intake during pregnancy, ultimately leading to improved maternal and fetal outcomes and health throughout the lifespan.