Epigenomics最新文献

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.

Background: A large scale detection of MLH1 methylation is lacking in esophageal cancer. MLH1 is a well-known mismatch repair gene. The mechanism of MLH1 in DNA double strand break (DSB) repair remains unclear.

Methods: Esophageal cancer cell lines and 1018 cases of primary cancer samples were employed. Methylation specific PCR, Western Blot, and CRISPR/Cas9 knockout technique were utilized.

Results: Methylation of MLH1 was detected in 3.93%. MLH1 methylation was significantly associated with tumor differentiation, male gender, smoking, and tumor size (all p < 0.05). The median overall survival (OS) was 24.7 months (95% CI 13.4-36.0) and 51.5 months (95% CI 40.4-62.5) in MLH1 methylated and unmethylated groups, respectively. OS was shorter in MLH1 methylated compared to unmethylated group patients (p < 0.01). Multivariate factor analysis indicated that MLH1 methylation is an independent poor prognosis marker (p < 0.05). MLH1 promotes ataxia telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR), and non-homologous end-joining repair (NHEJ), while inhibiting microhomology-mediated end joining (MMEJ) repair signaling pathways. Deletion of MLH1 sensitized esophageal cancer cells to novobiocin.

Conclusions: MLH1 plays important roles in DSB repair and deletion of MLH1 sensitizes ESCC cells to Polθ inhibitor.

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females, caused by mutations in the X-linked gene MECP2. This gene encodes methyl CpG binding protein 2 (MeCP2), a multifunctional epigenetic regulator critical for neuronal gene regulation. In addition to well-characterized neurological symptoms, such as seizures and motor abnormalities, RTT patients frequently present with irregular breathing patterns that induce intermittent hypoxia, suggesting that MeCP2 contributes to respiratory regulation as well as the brain's cellular and molecular response to hypoxia. Mechanistically, MeCP2 appears to influence hypoxia-induced expression of the neuroprotective peptide brain-derived neurotrophic factor (BDNF), as impaired BDNF regulation in MeCP2-deficient neurons contributes to hypoxia vulnerability. RTT patients also display increased oxidative stress, marked by elevated lipid peroxidation, DNA damage, and reduced antioxidant production. Dysfunctional mitochondria in MeCP2-deficient astrocytes and neurons further propagate oxidative damage and non-cell-autonomous effects of MeCP2 loss. Moreover, recent transcriptomic studies revealed widespread transcriptional dysregulation in RTT, including pathways associated with mitochondrial function and oxidative stress. We review and discuss an expanded role for MeCP2 as a critical integrator of hypoxia sensing, oxidative stress regulation, and transcriptional adaptation in the developing brain, offering new insights into treatments targeting the complex pathophysiology of RTT.

Paternal exposure to the environment can influence offspring phenotypes via a process known as intergenerational epigenetic inheritance. Such form of inheritance involves the sperm epigenome that is subjected to modifications by paternal exposure, which are carried from the father to the next generation. After fertilization, paternally inherited changes can manifest in the embryo and result in modified phenotypes later in life. To be long-lasting, these changes must either persist, escape the epigenetic reprogramming occurring after fertilization or be reinstated by guiding mechanisms during early development. This review discusses how the sperm epigenome instructs transcription and early embryonic development, and how environmental exposure can reshape this epigenetic information to influence developmental and transcriptional programs in the embryo. It addresses the patterns of penetrance in intergenerational epigenetic inheritance and considers how the sperm and embryonic epigenome can contribute to the variability of inherited phenotypes.

High-grade gliomas (HGGs), including glioblastoma and diffuse midline glioma, highlight one of the most aggressive brain tumors in adults and children with dismal prognosis despite intensive treatment regimens. Recently, epigenetic dysregulation has emerged as a fundamental hallmark of HGG biology, and the epigenetic alterations contribute not only to the molecular classification of HGGs but also to their malignant functional biology. Another notable feature of epigenetic dysregulation in HGGs is its influence on intratumoral heterogeneity, via possible modification of the neuron-glioma network in the brain. In this review, we aim to compile recent advances in our understanding of epigenetic dysregulation in HGGs, focusing on key mechanisms such as DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs. Furthermore, we will update our knowledge on the unexpected biology of glioma interaction with neuronal components from a standpoint of epigenetic heterogeneity. By discussing the epigenetic landscape of HGGs, we aim to provide a framework for future research and therapeutic innovation in the management of these devastating tumors.

Epigenomics has become multi-faceted, with researchers exploring chromatin structure, nucleosome states, and epigenetic modifications, producing large, complex multi-omic datasets. Given this shift, there is a demand for bioinformatics that leverage high-performance computing (HPC) and parallelization to quickly process data. As such, we developed SLUR(M)-py, a pythonic computational platform that leverages the Simple Linux Utility for Resource Management system (SLURM) to process sequencing data. SLUR(M)-py is multi-omic and automates calls to SLURM for processing paired-end sequences from chromatin characterization experiments, including whole-genome, ChIP-seq, ATAC-seq, and Hi-C, thereby eliminating the need for multiple analytics pipelines. To demonstrate SLUR(M)-py's utility, we employ ATAC-seq and Hi-C data from viral infection experiments and the ENCODE project, and illustrate its processing speed and completeness, which outpaces current HPC pipelines. We explore the effect of dropping duplicate sequenced reads in ATAC-seq, demonstrate how SLUR(M)-py can be used for quality control, and how to detect artifacts in Hi-C from viral infection experiments. Finally, we show how features in SLUR(M)-py, like inter-chromosomal analysis, can be used to explore the dynamics of chromosomal contacts in mammalian cells. This multi-omic, system-agnostic platform eases the computational burden for researchers and quickly produces accurate and reliable data analytics for the epigenomics community.

The intrinsic and acquired resistance of ovarian cancer to conventional platinum/taxane chemotherapy is approximately 80-85%, with a high recurrence rate, making it one of the most lethal gynecological cancers. Epigenetic dysregulation, a key factor in tumor growth and chemoresistance, includes abnormal DNA methylation and 5-hydroxymethylcytosine (5hmC) loss. The ten-eleven translocation (TET) family of dioxygenases (TET1/TET2/TET3) mediates DNA demethylation, causing oxidation of 5-methylcytosine to 5hmC, potentially altering gene expression due to cancer cell plasticity and impacting treatment responses. This review discusses the multiple effects of TETs in ovarian cancer, highlighting the regulation of epithelial mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin and TGF-β signaling pathways by TET enzymes. TET1 plays a dual role, promoting chemoresistance via CSC enrichment and suppressing tumors by replenishing Wnt antagonists. TET2, primarily a tumor suppressor, reduces 5hmC; TET2 loss is associated with poor therapeutic results. Elevated expression of TET3, which controls EMT and miRNA expression, is linked to a worse prognosis. In addition, we reviewed the potential resensitization of resistant tumors to multiple modalities of treatment by reactivating/modulating TET activity and function via cofactors and epigenetic treatment. Regulation of the TET-5hmc axis appears promising to overcome chemoresistance and improve therapeutic outcomes.

Epigenetic clocks are machine-learning algorithms which use DNA methylation patterns to predict aging-related phenotypes, such as chronological age, composite indicators of health, time-to-death, and the pace of biological aging. These clocks have been instrumental at the population level in revealing how disease risk emerges from behavioral, environmental, and psychosocial factors, and how certain anti-aging interventions may alter those trajectories. Given the success of epigenetic clocks at the population level, it is reasonable to assume they might also hold value as individual-level biomarkers. We contend, however, that fundamental technical and biological properties of these algorithms prohibit their current use at the individual level. Technical concerns include methods of clock construction, sample collection and processing, data preprocessing, and computational implementations. Biological considerations include the nature of DNA methylation and its dynamics, variation across developmental periods, tissue specificity, and sensitivity to environmental/sociodemographic contexts. We show that clocks fail to meet common standards for clinical utility compared with established biomarkers, and that applying epigenetic clocks in individual-level decision making can be uninformative and potentially harmful. Finally, we argue that even if all technical and biological hurdles can be overcome, epigenetic clocks, as we currently understand them, should not be used to make individual-level decisions.

Aim: Ketamine antidepressant effects go beyond immediate receptor action, involving lasting transcriptional and epigenomic changes that support its rapid, long-lasting benefits. The present systematic review synthesized existing preclinical and clinical evidence on the epigenetic mechanisms of ketamine in the treatment of depression.

Methods: A comprehensive search of three electronic databases was conducted through April 2025. Of 264 records screened, 18 studies met inclusion criteria most of which were preclinical. The study protocol was registered with PROSPERO (CRD420251063429).

Results: Most preclinical studies (n = 7) consistently showed that ketamine may modulate histone acetylation and methylation, boosting transcription of neuroplasticity-related genes. Six studies implicated non-coding RNAs - particularly microRNAs - in sustaining antidepressant effects. Five studies reported that ketamine reversed promoter hypermethylation in genes linked to synaptic signaling and stress, including brain-derived neurotrophic factor, restoring their expression. These effects were strongest in brain areas key to emotional regulation, like the hippocampus, medial prefrontal cortex, and nucleus accumbens. Indirect epigenetic mechanisms have been implicated in the regulation of circadian clock and inflammatory genes.

Conclusions: Ketamine may exert multilayered epigenetic modulation, leading to the reactivation of key neuroplasticity pathways. Although preclinical findings were strong, limited human data highlighted the need for translational studies to determine the clinical relevance of these mechanisms.

Alterations of the DNA methylation (DNAm) status of the genome underlie an increasing number of rare diseases. Recently, DNAm has also emerged as a highly informative biomarker for diagnosing rare disorders, which can be associated with distinctive genome-wide DNAm patterns (i.e., episignatures). Indeed, episignature testing has proven to represent an effective orthogonal omics technology, providing independent functional evidence to support or prioritize specific diagnostic hypotheses for hundreds of rare diseases, and reclassify variants of uncertain significance (VUS) emerging from genomic sequencing. Furthermore, the stability and plasticity inherent in DNAm make it a promising tool for personalized medicine, including patient stratification and therapeutic monitoring. This review outlines current technologies and analytical methodologies for genome-wide DNAm profiling and explores potential avenues of research, emphasizing artificial intelligence and multiomics integration to effectively manage patients with rare and complex phenotypes. We critically assess the current limitations and future directions of genome-wide DNAm profiling to expand the implementation of DNAm signatures as functional biomarkers, highlighting their importance as supplementary tools to genomic sequencing in clinical and research settings.