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Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density.

Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (NDiscovery  = 4614, NValidation  = 901). We associated methylation at multiple cytosine-phosphate-…

Epigenomic correlates of co-morbid psychosis in 22q deletion syndrome.

PURPOSE: 22q11.2 deletion syndrome (22q11DS) confers one of the strongest genetic risks of psychiatric disorders, with up to 25% of 22q11DS patients developing symptoms of psychosis. The broad phenotypic spectrum, variable deletion size, and lack of a defined pathogenic mechanism make it likely that 22q11DS phenotypes are mediated by non-genetic factors, such as epigenetics. METHODS: We developed a DNA methylation (DNAm) signature for 22q11DS in whole blood from 41 individuals with the common 2.54Mb 22q11.2 deletion and 42 matched controls using the Illumina MethylationEPIC v.2.0 array. We us

Integrative Genomic and Epigenomic Dissection of Facial Morphology in Chinese Populations.

Facial morphology is a highly heritable human trait, yet its underlying genetic architecture remains largely unresolved despite recent progress from genome-wide association studies (GWAS). Here, we integrated univariate and multivariate analyses of 230 facial phenotypes with GWAS and epigenome-wide association studies to identify genomic and epigenomic markers influencing facial variation in Chinese populations. Univariate analyses identified 144 single nucleotide polymorphisms (SNPs) and 34 CpG methylation sites, whereas multivariate canonical correlation analyses detected an additional 80 SN…

Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.

BACKGROUND: Epigenomic testing complements sequence-based analysis by detecting downstream changes in epigenomic state associated with genetic variation. Genome-wide DNA methylation episignatures are reproducible molecular phenotypes that can serve as biomarkers of specific Mendelian disorders, particularly those involving chromatin regulators, DNA methylation machinery, and transcriptional regulatory pathways. METHODS: We reviewed the biological basis, laboratory methodology, analytical approaches and clinical applications of DNA methylation episignature testing, with emphasis on neurodevelo

Integrated epigenomic and transcriptomic analyses implicate Car5b in cardiomyocyte hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy is a major risk factor for heart failure and is characterized by transcriptional and metabolic remodeling. Although chromatin accessibility is closely associated with transcriptional regulation, how accessibility changes relate to gene-expression and functional changes during hypertrophic stress remains incompletely understood. METHODS: Integrated ATAC-seq and RNA-seq analyses were performed in control and AngII-treated cardiomyocytes, followed by pathway enrichment and mitochondrial gene annotation. Candidate genes were validated in transverse aor

Epigenomic Landscape of Oak (Quercus robur) across Season and Generation.

Seasonal fluctuations strongly shape the physiology of long-lived trees by coordinating growth, dormancy, and stress responses. Increasing evidence points to epigenetic mechanisms, particularly DNA methylation, as regulators of these processes, yet their role in long-lived trees across seasons, developmental stages and generations remains poorly understood. We generated single-base resolution maps of cytosine methylation exploring the epigenetic landscape of 180 year-old mature oak (Quercus robur) trees (genetically homogeneous) along spring, summer and autumn, and in their progeny. Genome-wid

Disentangling covariate effects on single-cell-resolved epigenomes with DeepDive.

Understanding the effects of individual biological factors from single-cell-resolved epigenomic data is hindered by multicollinearity, particularly in human cohorts. We introduce DeepDive, a deep-learning framework designed to systematically disentangle known and unknown sources of variation in single-nucleus ATAC-seq data. DeepDive accurately reconstructs chromatin accessibility, outperforms state-of-the-art methods with incomplete covariate information, and robustly recovers true biological signals from even highly entangled covariates, unlocking counterfactual, "what-if," analyses. Applying

Fasting and aging: Mechanistic insights into epigenomic and transcriptional regulation of healthspan.

Fasting is an effective physiological intervention eliciting global and cellular adaptations that can improve healthspan and lifespan. In addition to its metabolic effects, fasting is a state of modulation of aging-associated processes/adaptive cellular responses that drives an intense epigenomic and transcriptional remodeling response which preserves functional capacity during aging. Nutrient deprivation elicits the activation of evolutionarily conserved nutrient-sensing pathways including AMPK and sirtuins, which can modulate chromatin accessibility and transcriptomic programs. These changes

Epigenomics and Ayurgenomics: Molecular Analysis of Ayurvedic Prakriti in Personalized Healthcare.

Personalized healthcare increasingly requires models that explain individual variation in disease risk, prevention, and treatment response. Ayurvedic Prakriti offers a constitution-based framework for classifying human variability through Vata, Pitta, and Kapha phenotypes, while Ayurgenomics attempts to connect these traditional classifications with molecular biology. Despite growing interest, the biological relationship between Prakriti, epigenomic regulation, and precision healthcare remains insufficiently established, particularly because available evidence is limited by small cohorts, hete

Dominant clones leverage developmental epigenomic states to drive ependymoma.

ZFTA-RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA-RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible ch

Initial leukemic epigenomic state determines hypomethylating agent response.

Hypomethylating agents (HMAs) are a mainstay of therapy for myeloid cancers, but genetic biomarkers do not predict who will respond to treatment. Using a variety of single-cell sequencing approaches to define the epigenomic state of responder and nonresponder leukemic cells, we demonstrate that leukemic stem cells (LSC) exist in at least two different epigenomic states: a hematopoietic stem cell (HSC)-or multipotent progenitor (MPP)-like state that is sensitive to HMAs, independent of genetic mutations, or a lymphoid-primed MPP (LMPP)-like nonresponder state. Hypomethylation and chromatin acce

Decoding Waldenström Macroglobulinemia Through Genomics, Epigenomics and Cellular Interactions

Waldenström macroglobulinemia is a rare lymphoplasmacytic malignancy characterized by bone marrow infiltration and monoclonal immunoglobulin M production. Despite its indolent clinical course, the disease exhibits considerable biological complexity driven by recurrent genetic alterations, dysregulated signaling pathways, and a supportive bone marrow microenvironment. The identification of MYD88 and CXCR4 mutations has significantly advanced understanding of disease pathogenesis, clonal evolution, and treatment response. Additional insights from cytogenetic, epigenetic, and microRNA studies hav

Epigenomic Dysregulation in Youth Vapers: Implications for Disease Risk Assessment.

Despite the ongoing epidemic of youth vaping, the long-term health consequences of electronic cigarette use are largely unknown. We report the effects of vaping versus smoking on the oral cell methylome of healthy young vapers and smokers relative to nonusers. Whereas vapers and smokers differ in the number of differentially methylated regions (DMRs) (831 vs. 2,863), they share striking similarities in the distribution and patterns of DNA methylation, chromatin states, transcription factor binding motifs, and pathways. There is substantial overlap in DMR-associated genes between vapers and smo

Duckweed genomes and epigenomes underlie triploid hybridization and clonal reproduction.

The Lemnaceae (duckweeds) are the world's smallest but fastest-growing flowering plants. Prolific clonal propagation facilitates continuous micro-cropping for plant-based protein and starch production and holds tremendous promise for sequestration of atmospheric CO2. Here, we present chromosomal assemblies, annotations, and phylogenomic analysis of Lemna genomes that uncover candidate genes responsible for the unique metabolic and developmental traits of the family, such as anatomical reduction, adaxial stomata, lack of stomatal closure, and carbon sequestration via crystalline calcium oxalate

Precision medicine for asthma treatment: Unlocking the potential of the epigenome and microbiome.

Asthma is a leading worldwide biomedical concern. Patients can experience life-threatening worsening episodes (exacerbations) usually controlled by anti-inflammatory and bronchodilator drugs. However, substantial heterogeneity in treatment response exists, and a subset of patients with unresolved asthma carry the major burden of this disease. The study of the epigenome and microbiome might bridge the gap between human genetics and environmental exposure to partially explain the heterogeneity in drug response. This review aims to provide a critical examination of the existing literature on the …

Molecular pathological approach to cancer epigenomics and its clinical application.

Careful microscopic observation of histopathological specimens, accumulation of large numbers of high-quality tissue specimens, and analysis … liquid chromatography-based diagnostic system for DNA methylation diagnosis. Research on the cancer epigenome has revealed that DNA methylation alterations occur from the precancerous stage as a result of exposure to carcinogenic factors such as inflammation, smoking, and viral infections, and continuously contribute to multistage carcinogenesis through abe …

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective.

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… Particularly, the neuronal epigenome is highly sensitive to external stimuli and its function is required for learning and memory processes (Creighton et al., 2020). … Furthermore, exercise and brain stimulation can modify the neuronal epigenome, enhancing synaptic plasticity. …

The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes.

The autoimmune disease, Type 1 Diabetes Mellitus (T1DM), results in the destruction of pancreatic β-cells, and the International Diabetes Fe … components as potential triggers for epigenetic modifications. Clarifying the link between diet and epigenome can provide new insights into the pathogenesis of T1DM, potentially leading to new diagnostic and therapeutic approaches. In this mini review, we shed light on the influence of the diet-epigenome axis on the pathophysiology of T1DM.

The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination.

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Sim…

Epigenomic Landscape of Lyme Disease Spirochetes Reveals Novel Motifs.

Borrelia burgdorferi, the etiological agent of Lyme disease, persists in nature through an enzootic cycle consisting of a vertebrate host and an Ixodes tick vector. The sequence motifs modified by two well-characterized restriction/modification (R/M) loci of B. burgdorferi type strain B31 were recently described, but the methylation profiles of other Lyme disease Borrelia bacteria have not been characterized. Here, the methylomes of B. burgdorferi type strain B31 and 7 clonal derivatives, along with B. burgdorferi N40, B. burgdorferi 297, B. burgdorferi CA-11, B. afzelii PKo, B. afzelii BO23,