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Results for “Epigenetic reprogramming”

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PubMed2026

Genome-wide H3K4me3 profiling of circulating immune cells reveals dynamic epigenetic reprogramming during acute critical COVID-19.

INTRODUCTION: Severe COVID-19 is associated with innate immune dysregulation resembling sepsis-induced immunoparalysis. Epigenetic mechanisms, particularly changes in H3K4me3 enrichment at gene promoters, have been observed in immune tolerance and monocyte dysfunction in sepsis. Whether comparable H3K4me3 alterations occur during acute critical COVID-19 illness has not been investigated. METHODS: In this prospective single-center study, 46 hospitalized COVID-19 patients were enrolled, of whom 27 were treated in the intensive care unit (ICU group) and 19 on the normal ward (non-ICU group). Genome-wide H3K4me3 ChIP-seq was performed on PBMCs at hospital admission (T1) in the total cohort and after seven days (T2) in the ICU group. Monocyte HLA-DR expression and ex vivo TLR-stimulated cytokine secretion were assessed as functional immune readouts. RESULTS: Among 706 differentially bound consensus peaks with promoter association between ICU and non-ICU groups, 704 showed increased H3K4me3 occupancy in ICU patients, predominantly at neutrophil effector gene loci, supported by pathway enrichment of neutrophil degranulation and innate immune activation. Monocyte HLA-DR expression and ex vivo TLR-stimulated IL-6 secretion were persistently reduced throughout the first week of ICU treatment. Longitudinal profiling in the ICU group revealed a shift from an interferon-driven chromatin signature at admission toward sustained innate immune activation and ECM remodeling at day seven. CONCLUSION: This study provides the first genome-wide H3K4me3 characterization of circulating immune cells during acute critical COVID-19, demonstrating that epigenetic reprogramming is an active and dynamic process that mirrors the functional immune dysregulation observed in these patients.

Humans↗

PubMed2026

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects.

PURPOSE: Early human embryogenesis unfolds through a tightly coupled sequence of events-clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post-implantation patterning-accompanied by epigenetic reprogramming, including X-chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. METHODS: I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single-cell genomics and stem-cell-based embryo modeling, and integrate these insights to identify human-specific features of early development. RESULTS: These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species-specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X-chromosome dosage compensation. CONCLUSIONS: Advances in single-cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next-generation embryo selection strategies.

Journal Article↗

PubMed2026

Oxidative stress-driven epigenetic reprogramming of immune cells in COPD: from epitranscriptomic and metabolic crosstalk to treatable traits.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by persistent oxidative stress and maladaptive immune responses, rather than a single disease entity. Oxidative stress not only damages lung tissue but also reprograms immune cells through both classical epigenetic mechanisms (DNA methylation, histone modifications) and epitranscriptomic regulation (m6A RNA methylation), shaping disease endotypes and treatment resistance. This review presents an integrated framework in which redox signals dynamically reshape the epigenetic and epitranscriptomic landscape, thereby locking immune cells into pathogenic states. Metabolic intermediates (S-adenosylmethionine, α-ketoglutarate, succinate, NAD+) serve as critical nodes that connect immunometabolism to both classical epigenetic enzymes and the m6A machinery, thereby linking redox status to RNA fate. Using NETosis as a paradigm, we illustrate how oxidative-epigenetic-metabolic loops sustain neutrophilic inflammation and resolution failure. Finally, we outline a treatable traits framework that integrates these mechanistic insights into precision combination therapies. This conceptual roadmap aims to shift COPD management from symptom control toward durable, mechanism-driven disease modification.

Humans↗

PubMed2026

Chronic psychological stress potentiates IgE class switch recombination via glucocorticoid receptor-mediated epigenetic reprogramming of B cells.

BACKGROUND: Chronic psychological stress is a well-recognized factor in the exacerbation of allergic diseases, with IgE playing a central role in their pathophysiology. However, the exact molecular mechanisms by which stress hormones directly influence IgE production and contribute to allergic responses remain largely uncharacterized. OBJECTIVE: This study aimed to elucidate the direct mechanisms through which chronic psychological stress, via elevated cortisol, regulates IgE class switch recombination (CSR) in B cells and contributes to stress-aggravated allergic inflammation in vivo. METHODS: We employed a chronic restraint stress (CRS) mouse model to investigate the impact of psychological stress on humoral immunity. In vitro experiments utilized primary murine B cells treated with physiological cortisol concentrations (250 nM), incorporating molecular techniques such as CRISPR-Cas9-mediated gene knockdown, chromatin immunoprecipitation (ChIP), whole-genome bisulfite sequencing, and pharmacological inhibitors of epigenetic enzymes. Primary human B cells and the U266 human myeloma cell line were used for translational validation. In vivo validation was performed using an ovalbumin (OVA)-induced allergic airway inflammation model with B cell-specific glucocorticoid receptor (GR) knockout mice. RESULTS: Chronic psychological stress significantly elevated plasma corticosterone and serum IgE levels in mice, with no changes in IgG1 or IgM. In purified in vitro B-cell cultures, cortisol promotes epigenetic remodeling at the Iε promoter region and enhances Iε germline transcript expression in an isotype-specific manner, and this effect was recapitulated in human B cells. GR bound to the Iε promoter's Amp_1 region (-154 to -62 bp), and CRISPR-Cas9-mediated GR knockdown abolished cortisol-induced IgE production. Mechanistically, cortisol increases enrichment of activating histone marks (H3K27ac, H3K4me3) and reduces H3K27me3 at the Iε promoter region, and induces site-specific DNA hypomethylation; inhibition of histone acetyltransferases (HATs) or DNA demethylation attenuated this effect. In vivo, B cell-specific GR knockout completely abrogated stress-induced exacerbation of allergic airway inflammation, including elevated serum IgE, eosinophilic inflammation, and airway hyperresponsiveness (AHR). CONCLUSION: Our findings support a mechanistic model in which chronic psychological stress, through elevated glucocorticoids, acts via GR to promote epigenetic remodeling at the Iε promoter region in B cells to enhance IgE synthesis and exacerbate allergic responses. This study provides a critical molecular link between the neuroendocrine system and adaptive immunity, offering promising therapeutic targets for stress-aggravated IgE-mediated diseases.

Animals↗

PubMed2026

Transmitochondrial pigs reveal causal effects of mitochondrial DNA on backfat thickness via nuclear epigenetic reprogramming.

Mitochondrial DNA (mtDNA) polymorphisms have been associated with production traits in farm animals, including backfat thickness in pigs, yet direct in vivo evidence establishing a causal link between specific mtDNA haplotypes and fat deposition remains limited. In this study, we generated transmitochondrial pigs (mitopigs) by combining the Dapulian nuclear genome with Wuzhishan mtDNA via somatic cell nuclear transfer, introducing 23 mtDNA mutations relative to controls. Mitopigs exhibited significantly increased backfat thickness at 5 months, a difference that persisted in their offspring, without significant differences in body weight, body size, or litter size. Fibroblasts derived from mitopigs exhibited reduced mtDNA copy numbers, decreased expression of mitochondrial biogenesis genes (PPARA, PPARGC1A, RRM2B, and LRPPRC), impaired mitochondrial respiration, elevated reactive oxygen species (ROS), and upregulated adipogenic transcription factors (CEBPA, CEBPB, and PPARG). Consistent with these fibroblast findings, backfat tissue of mitopigs showed corresponding upregulation of adipogenic transcription factors and downregulation of mitochondrial biogenesis genes. Integrated transcriptomic and whole-genome bisulfite sequencing (WGBS) analyses revealed nuclear transcriptional reprogramming that was closely associated with differential DNA methylation, predominantly affecting mitochondrial function and lipid metabolism pathways. Mitopig fibroblasts also showed a pro-inflammatory response to lipopolysaccharide stimulation, with elevated expression of IL-12, NOS2, RELA, and TNF-α. Our findings provide direct in vivo evidence that mtDNA variants regulate adiposity in pigs through mitochondrial dysfunction, oxidative stress, and nuclear epigenetic modulation, highlighting the potential for incorporating mtDNA haplotype information into pig breeding programs as a complementary strategy to nuclear genomic selection.

Adipogenesis↗

PubMed2026

Maternal high-fat diet modulates lupus nephritis through fetal Wnt-steroid hormone and epigenetic reprogramming in MRL/lpr mouse offspring.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Axin2↗

PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗

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↗

PubMed2026

Epigenetic reduction OF H3K9me3 and H3K27me3 by RK-701 and GSK 126 improves the developmental competence of bovine SCNT embryos.

Somatic cell nuclear transfer (SCNT) failure has largely been attributed to incomplete epigenetic reprogramming, particularly the dysregulation of repressive histone modifications such as H3K9me3 and H3K27me3. Reducing these repressive marks has been shown to improve reprogramming efficiency in SCNT embryos. Although histone demethylase mRNA injection has been used for this purpose, it is labor-intensive, technically demanding, and time-consuming. In this study, we investigated a simplified approach that combined RK-701 and GSK-126 to reduce H3K9me3 and H3K27me3 levels, respectively, in bovine SCNT embryos. Three experimental groups were established: IVF embryos (control), SCNT-control (SCNT-C) embryos, and inhibitor-treated SCNT embryos (SCNT-T). The IVF group was used as a reference standard. Fused one-cell SCNT embryos were treated with 2 μM RK-701 and 0.2 μM GSK-126 from the one-cell stage to the 16-cell stage. Gene expression analysis at the 16-cell stage revealed a significant reduction in histone methyltransferase (HMT) expression (p < 0.05), and immunofluorescence analysis confirmed marked decreases in H3K9me3 and H3K27me3 levels. In addition, the expression of genes associated with zygotic genome activation (ZGA) and pluripotency was significantly higher in SCNT-T embryos than in SCNT-C embryos. Assessment of blastocyst quality revealed reduced reactive oxygen species (ROS) levels, decreased expression of apoptosis-related genes, and improved mitochondrial membrane potential in the treated group, as indicated by JC1 staining. Overall, this approach effectively reduced repressive histone marks, enhanced epigenetic reprogramming, and improved ZGA, thereby increasing the developmental rate and adhesion potential of bovine SCNT embryos. These findings suggest that combined treatment with RK-701 and GSK-126 may provide a simple and practical strategy for improving the efficiency of bovine cloning.

Bovine embryos↗

PubMed2026

Transcriptomic and network analyses identify epigenetic regulators of drug-tolerant persister (DTP) subsets in EGFR-mutant HCC827 non-small cell lung cancer.

BACKGROUND: The clinical efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by the inevitable acquired resistance. Drug-tolerant persister (DTP) cells, which survive initial therapy, are considered a key reservoir for this resistance. Understanding the molecular characteristics of DTPs is essential for developing strategies to prevent relapse. OBJECTIVE: This study aimed to characterize the transcriptomic landscape of osimertinib-tolerant DTP cells and identify key epigenetic regulators associated with the DTP phenotype in EGFR-mutant HCC827 NSCLC cells through integrated transcriptomic and network analyses. METHODS: We established an in vitro model of osimertinib tolerance using an EGFR-mutant (exon 19 deletion) HCC827 NSCLC cell line. Parental HCC827 cells and DTP subsets were subjected to transcriptomic analysis by RNA sequencing (RNA-seq). Differentially expressed genes were identified, followed by bioinformatics analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses to identify key biological processes driving the DTP phenotype. Key findings were validated using quantitative real-time PCR (qPCR). RESULTS: Osimertinib treatment induced a morphologically distinct DTP population. Transcriptomic profiling revealed a marked shift in gene expression compared to parental cells. Functional enrichment analysis showed significant upregulation of epigenetic pathways. PPI network analysis identified a core module of eight hub genes, including histone deacetylases (HDAC5, HDAC9), sirtuins (SIRT1, SIRT2), and histone acetyltransferase (KAT2B). qPCR confirmed increased expression of HDAC5, HDAC9, and SIRT1. CONCLUSION: Epigenetic reprogramming accompanies the transition to an osimertinib-tolerant state in EGFR-mutant HCC827 cells. Targeting HDACs and sirtuins may represent a promising strategy to eliminate DTP subpopulations and delay or prevent acquired resistance.

Drug-tolerant persister↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2026

Epigenetic alterations induced by ionizing radiation: pathways to cancer and prognostic strategies.

PURPOSE: Ionizing radiation (IR) is widely used not only in cancer diagnosis and therapy, but its biological effects also extend beyond radiation-induced lethal lesions, e.g., specifically DNA double-strand breaks (DNA-DSBs). This review aims to summarize current evidence on IR-induced epigenetic alterations and to integrate mechanistic insights from radiation chemistry and radiation biology that link DNA damage to long-term epigenetic dysregulation. RESULTS: Experimental and clinical studies collectively show that IR induces persistent epigenetic reprogramming, including global and gene-specific DNA methylation changes, radiation-responsive histone modifications, chromatin remodeling, and dysregulation of non-coding RNAs. Aberrant RNA methylation, including modifications like N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanine (m7G), and N3-methylcytosine (m3C), is closely linked to tumorigenesis and progression. Due to its tumor-specific properties, RNA methylation markers, specifically m6A, m5C, m1A, m7G, and m3C, emerge as valuable markers in liquid biopsy. Radiation chemistry studies indicate that epigenetically modified bases, for example, m5C, are preferential targets of radiation-induced oxidative damage, thereby promoting mutational hotspots and genomic instability. By altering DNA repair, apoptosis, immune responses, and cellular differentiation, these epigenetic changes promote carcinogenesis, radioresistance, and tissue toxicity. CONCLUSION: IR-induced epigenetic alterations represent a critical interface between initial DNA damage and long-term biological outcomes. Improved understanding of radiation-associated epigenetic signatures may enhance risk assessment, inform prognostic stratification, and support the development of epigenetic-targeted strategies to optimize radiotherapy and reduce adverse effects.

Ionizing radiation↗

PubMed2026

Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos.

BACKGROUND: The maternal-effect protein PADI6, which is part of the subcortical maternal complex, is involved in proper spindle assembly, organelle distribution, ribosome storage, and cytoplasmic lattice organization in mouse oocytes. In humans, variants of PADI6 are associated with female infertility and multilocus imprinting disturbance in offspring. Recently, it was demonstrated that PADI6 plays a role in the storage and cytoplasmic localization of epigenetic factors, including UHRF1 and DNMT1. Moreover, maternal PADI6 depletion leads to defective epigenetic reprogramming and zygotic genome activation but not to an imprinting defect in two-cell mouse embryos. These findings raise the possibility that imprinting disturbances arise later in development. RESULTS: By employing combined single-blastocyst RNA-seq/BS-seq and immunostaining validation in the embryos derived from Padi6P620A-mutant oocytes, we investigated the role of Padi6 in late preimplantation development. We demonstrated that embryos that overcame the two-cell stage block had a dramatic reduction in UHRF1 and DNMT1 protein levels, a decrease in H3K9me3, and whole-genome hypomethylation, including most imprinted loci and repetitive elements, at the blastocyst stage. Furthermore, these maternal mutant embryos showed deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. CONCLUSION: Our results demonstrate that maternal PADI6 is a key regulator of the stability of epigenetic factors required to maintain repressive marks in late preimplantation mouse embryos. Its deficiency results in genomic imprinting defects that closely resemble those found in human patients and provide a mechanistic explanation for MLID caused by maternal PADI6 variants. Furthermore, the impairment of blastocyst implantation capacity, likely due to dysregulation of inner cell mass differentiation, provides new mechanistic insights into the control of female fertility and embryo development exerted by PADI6.

DNA Methylation↗

PubMed2025

Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing.

Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control the expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.

Prader-Willi Syndrome↗

PubMed2026

Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.

Innate immune memory enables non-vertebrates to mount faster and more effective immune responses upon re-exposure to a previously encountered pathogen, yet its cellular and molecular bases remain poorly understood. The freshwater snail Biomphalaria glabrata, intermediate host of the human parasite Schistosoma mansoni, provides a powerful model to investigate this phenomenon. Here, we show that innate immune memory in B. glabrata is carried by hemocytes and relies on profound metabolic and epigenetic reprogramming initiated during primary infection. Using an integrative multi-omics approach combining transcriptomics, chromatin accessibility profiling, whole-genome bisulfite sequencing and targeted metabolomics, we reveal that the first parasite encounter induces a stable rewiring of hemocyte metabolism and chromatin landscape. This reprogramming primes hemocytes for a massive and rapid transcriptional response upon secondary challenge, characterized by an immune shift toward highly specific humoral effector pathways. Metabolic analyses demonstrate an early switch toward aerobic glycolysis, altered tricarboxylic acid cycle activity and amino acid metabolism, consistent with a Warburg-like metabolic state previously described in vertebrate trained immunity. Notably, metabolic and epigenetic remodeling occurs primarily during the primary infection and remains stable upon secondary exposure, suggesting that immune memory is encoded prior to pathogen re-encounter. Together, our results identify conserved metabolic and epigenetic mechanisms underlying innate immune memory in a non-vertebrate host and provide direct evidence that hemocyte-mediated innate immune memory in B. glabrata shares core features with trained immunity described in vertebrates.

Animals↗

PubMed2026

Epigenetic and Transcriptional Regulatory Networks Underlying Psoriasis Pathogenesis.

Psoriasis is a chronic, immune-mediated dermatologic disorder characterized by the hyperproliferation of keratinocytes and dysregulated immune signaling. Although genome-wide association studies have identified susceptibility loci, the multifactorial nature of the disease underlines the importance of nongenetic regulatory mechanisms. Among these epigenetic modifications are those that critically link genetic predisposition with environmental stimuli. This review offers an in-depth overview of the current insights into the role of epigenetic regulation in the pathophysiology of psoriasis. Key mechanisms, including aberrant DNA methylation, histone post-translational modifications (eg, H3K27ac, H3K4me3), and dysregulated noncoding RNAs, are discussed in the context of inflammatory signaling and immune cell function. This review also explores how environmental factors such as UV radiation and air pollution induce the epigenetic reprogramming that perpetuates the proinflammatory state. Furthermore, it highlights the translational potential of targeting epigenetic regulators and epigenome-editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR) fusion systems, as precision therapeutic strategies. In parallel, advances in single-cell epigenomics, spatial transcriptomics, and the profiling of circulating biomarkers offer novel diagnostic tools. Despite advances, challenges persist, including the limited predictive value of preclinical models and variable epigenetic profiles. Positioning epigenetics as the bridge between genetic risk, environmental triggers, and therapeutic advances, this review presents a framework for precision medicine in psoriasis.

Humans↗

PubMed2025

Machine learning on multiple epigenetic features reveals H3K27Ac as a driver of gene expression prediction across patients with glioblastoma.

Epigenetic mechanisms play a crucial role in driving transcript expression and shaping the phenotypic plasticity of glioblastoma stem cells (GSCs), contributing to tumor heterogeneity and therapeutic resistance. These mechanisms dynamically regulate the expression of key oncogenic and stemness-associated genes, enabling GSCs to adapt to environmental cues and evade targeted therapies. Importantly, epigenetic reprogramming allows GSCs to transition between cellular states, including therapy-resistant mesenchymal-like phenotypes, underscoring the need for epigenetic-targeting strategies to disrupt these adaptive processes. Understanding these epigenetic drivers of gene expression provides a foundation for novel therapeutic interventions aimed at eradicating GSCs and improving glioblastoma outcomes. Using machine learning (ML), we employ cross-patient prediction of transcript expression in GSCs by combining epigenetic features from various sources, including ATAC-seq, CTCF ChIP-seq, RNAPII ChIP-seq, H3K27Ac ChIP-seq, and RNA-seq. We investigate different ML and deep learning (DL) models for this task and ultimately build our final pipeline using XGBoost. The model trained on one patient generalizes to other 11 patients with high performance. Notably, H3K27Ac alone from a single patient is sufficient to predict gene expression in all 11 patients. Furthermore, the distribution of H3K27Ac peaks across the genomes of all patients is remarkably similar. These findings suggest that GSCs share a common distributional pattern of enhancer activity characterized by H3K27Ac, which can be utilized to predict gene expression in GSCs across patients. In summary, while GSCs are known for their transcriptomic and phenotypic heterogeneity, we propose that they share a common epigenetic pattern of enhancer activation that defines their underlying transcriptomic expression pattern. This pattern can predict gene expression across patient samples, providing valuable insights into the biology of GSCs.

Glioblastoma↗

PubMed2026

Paternal exposure to polystyrene nanoplastics induces inter- and transgenerational bronchopulmonary dysplasia-like damage in male offspring by FtMt hypermethylation-mediated ferroptosis.

Bronchopulmonary dysplasia (BPD) is a major cause of chronic lung disease in both preterm infants and adults, but its etiology remains incompletely understood. In this study, F0 generation mice were exposed to polystyrene nanoplastics (PS-NPs), and F1 to F3 generations were obtained by breeding. Multi-omics sequencing including whole genome methylation sequencing, single cell transcriptome sequencing and transcriptome sequencing was performed on the lungs of offspring. The levels of Fe2+, lipid peroxidation products and key gene expression were determined. Male mice exposed to PS-NPs at environmentally relevant doses produced offspring (F1 and F2) that exhibited a typical BPD-like phenotype. Meanwhile, the F0 males showed diminished sperm motility, demonstrating that paternal PS-NPs exposure constituted an etiological factor for BPD in descendants. Mechanistic studies showed that PS-NPs exposure upregulated the expression of DNA methyltransferase Dnmt3a, leading to global hypermethylation of the sperm genome. Importantly, the hypermethylated promoter signature of the mitochondrial ferritin (FtMt) gene partially resisted epigenetic reprogramming and was transmitted to the lungs of offspring, resulting in persistently low FtMt expression in F1 and F2 lungs. This led to increased intracellular Fe2+ levels, subsequently triggered ferroptosis in alveolar epithelial cells, and ultimately impaired alveolarization. Knockdown of FtMt confirmed that FtMt deficiency was sufficient to induce ferroptosis and BPD-like lung injury both in vitro and in vivo. Furthermore, using in vitro fertilization of F0 sperm combined with Dnmt3a siRNA microinjection, we directly demonstrated that Dnmt3a is a key driver for FtMt to escape reprogramming and maintain its hypermethylation. In summary, this study reveals for the first time that paternal PS-NPs exposure causes BPD through a Dnmt3a-FtMt hypermethylation intergenerational and transgenerational axis, providing an epigenetic basis for understanding paternal derived chronic lung disease and potential targets for early intervention.

Animals↗