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PubMed2026

AI-Based 3D Heterogeneous Network Model for Functional Prediction of Epigenetics.

Human biology and diseases are the result of constantly evolving processes within an intricately complex molecular network of interactions, such as epigenetic regulation. Epigenetics refers to heritable changes in gene expression that occur without alterations to the underlying DNA sequence. These changes, driven by mechanisms such as DNA methylation, histone modifications, and noncoding RNAs, play critical roles in regulating chromatin structure and gene activity. Epigenetic regulation offers valuable insights into biological systems, and when integrated with sophisticated analyses, it enables us to gain insights into gene regulation and cellular behavior. Here, we describe an artificial intelligence (AI)-based model that is capable of generating 3-dimensional (3D) heterogeneous network by integrating multimodal data for the functional prediction of epigenetic mechanisms, emphasizing its applications in medicine, developmental biology, and personalized therapeutics. Heterogeneous networks in biology are powerful tools for understanding the complex interactions and interdependencies within biological systems. Key advancements in AI and multiomics data integration have propelled this field, offering new insights into disease mechanisms, biomarker discovery, and therapeutic interventions.

Epigenesis, Genetic↗

PubMed2026

Culture, Psychiatry and Epigenetics.

Regarding the methodology of ethnopsychiatric research, for example, on the Vietnamese Mo Mường's burial rituals or the health-promoting and healing effects of the Chinese Tujia dances, three different approaches can be distinguished: phenomenological-descriptive methods, hermeneutic-interpretive techniques and studies on underlying mechanisms such as hypnotherapeutic or neuroendocrine dynamics. Since epigenetics has shown that cultural and artistic experiences can influence gene expression and genetic functioning, even across generations, the article argues for greater consideration of epigenetics in medical anthropology and ethnopsychiatry. Epigenetic dynamics can significantly influence health promoting and healing effects of rituals in ethnic traditions and determine an individual's responsiveness to such practices. In this context, the interplay between genetics and epigenetics, various concepts of the collective unconscious, transcultural psychiatry, culturally sensitive arts therapies, and issues of migration and transcultural identities are discussed.

Humans↗

PubMed2025

Genetic and Epigenetic Approaches to Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a major global-scale social issue affecting public health. The high potential for addiction and dependence makes opioid use a significant concern, contributing to substance-related disorders. Both genetic and environmental factors contribute to the predisposition to OUD, with the opioidergic, dopaminergic, and GABAergic systems playing primary roles in itsonset. METHODS: This narrative review documents the association between genes and their variants related to these three systems, along with current evidence on epigenetic interventions in OUD. Relevant studies investigating candidate-gene associations and molecular mechanisms were synthesized to highlight genetic variants and epigenetic processes linked to OUD. RESULTS: Genetic associations play a prominent role in OUD, with several single-nucleotide variants identified in affected populations. Key genes implicated include OPRM1, OPRD1, OPRK1, PDYN, OPRL1, and POMC from the opioidergic system; DRD1, DRD2, DRD3, DRD4, ANKK1, and COMT from the dopaminergic system; and GABRA2, GABRB3, GABRG2, GAD1, and GAD2 from the GABAergic system. Evidence also indicates that chronic opioid use is associated with epigenetic changes through posttranslational histone modifications and DNA methylation. However, limitations in existing studies include small sample sizes, limited replication, and potential stratification biases. CONCLUSIONS: Although many candidate-gene associations have been proposed for OUD, robust evidence remains limited. Large, ancestrally diverse genome-wide association studies (GWAS) and systematic replication studies are urgently needed. A deeper understanding of the genetic, epigenetic, and neurobiological bases of addiction will be essential for the development of precisely targeted medications to improve prevention and treatment outcomes for OUD.

Humans↗

PubMed2026

Beyond mutations: epigenetic and fragmentomic landscapes of cfDNA in lung cancer.

INTRODUCTION: Lung cancer is the most frequently diagnosed cancer worldwide and the leading cause of cancer-related mortality. Cell-free DNA (cfDNA) has emerged as a powerful biomarker in cancer detection. Early diagnostics efforts often leverage cancer-associated mutations present in cfDNA, but beyond such mutation-based assays, recent advances have shed light on other non-mutational features. The analysis of cfDNA epigenetic profiles and fragmentation patterns, known as 'fragmentomics,' has revealed a wealth of data to explore in noninvasive lung cancer diagnosis. AREAS COVERED: This review will explore this new narrative, summarizing the current understanding and use of cfDNA epigenetic modifications and fragmentomic patterns, while integrating findings to illustrate their vast potential in early-stage detection and therapeutics. By considering a range of epigenetic and fragmentomic features, cfDNA methylation (5mC, 5hmC), histone modifications, size profiles, and end signatures, this review highlights how the multidimensional integration of such signals shows promise in refining early-stage lung cancer and guiding therapeutic decisions. EXPERT OPINION: cfDNA epigenetic and fragmentomic analyses represent a transformative frontier in lung cancer diagnostics and monitoring. While these approaches demonstrate significant potential, most studies are limited by modest cohort sizes and reports of survival benefits, underscoring the need for large-scale validation and deeper mechanistic understanding.

Humans↗

PubMed2026

Epigenetic Gene Networks Governing Immune State Transitions Across the Lifespan.

Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accessed and resolved. Increasing evidence indicates that epigenetic gene networks regulate the accessibility and reversibility of semi-stable immune states, shaping plastic, homeostatic, reparative, and degenerative configurations. We propose the concept of epigenetic transition windows, defined as temporally and contextually restricted intervals during which epigenetic constraints are relaxed, permitting coordinated and reversible transitions between immune states. During development, these windows are broad and support immune tolerance and adaptive plasticity. In adulthood they become spatially and temporally restricted, preserving stability while enabling conditional adaptation. With aging, they progressively narrow, contributing to chronic inflammation, impaired repair, and increased vulnerability to neurodegeneration. Conversely, pathological persistence of regulatory permissiveness may underlie immune evasion and sustained plasticity in cancer. We outline operational genomic readouts for quantifying transition windows, including chromatin accessibility variance, enhancer switching dynamics, reversibility metrics, and cross-cell coordination indices, and derive experimentally testable predictions that distinguish this model from pathway-centric or damage-centric explanations. By reframing immune dysfunction as a failure of regulated state transition rather than excessive signaling alone, this framework integrates inflammaging, trained immunity, immune resolution failure, and tumor immune escape within a unified regulatory architecture and provides a systems-level perspective on immune adaptability across the lifespan.

Epigenesis, Genetic↗

PubMed2026

Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery.

Inflammaging represents a hallmark of biological aging, yet the causal inflammatory mediators driving multi-dimensional epigenetic aging and their effector genes remain poorly characterized at the genetic level. We developed a four-tier analytical framework integrating causal screening, multi-omics effector gene mapping, spatial transcriptomics, and drug target evaluation. Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes. Using multi-omics summary-based MR (SMR) as the core analytical engine, we integrated four-layer whole-blood molecular QTL resources eQTL (eQTLGen, n = 31,684), sQTL (GTEx, n = 755), pQTL (INTERVAL + SCALLOP, n = 34,232), and mQTL (McRae et al., n = 1,980) - with GWAS summary statistics for four epigenetic age acceleration measures. At a stringent threshold (P_SMR < 1×10⁻¹²), seven high-confidence effector genes were identified: NHLRC1, TPMT, SELP, and RIPPLY3 for IEAA; ZNF373A and PLDN for HannumAA; and EDARADD for PhenoAA. The chromosome 6p21 NHLRC1-TPMT locus, overwhelmingly driven by methylation QTL signals (-log₁₀P = 26.06), emerged as the dominant genetic node of epigenetic aging. Spatial projection via gsMap onto a mouse E16.5 embryo atlas (121,767 cells) revealed preferential enrichment in smooth muscle and lung, with EDARADD showing marked specificity in mucosal epithelium. Cross-database drug target mining classified TPMT and SELP as repurposable known targets and NHLRC1 as a high-priority novel druggable candidate. This study provides multi-omics convergent causal evidence for inflammation-driven epigenetic aging and delivers genetically anchored targets for precision anti-aging intervention.

Aging↗

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

Epigenetic profiling of circulating cell-free DNA for early detection and minimal residual disease assessment in lung cancer: a focus on DNA methylation.

Lung Cancer (LC) continues to be the biggest cause of cancer-related deaths around the world, mostly because of delayed diagnosis. Even if tissue biopsies and circulating tumor DNA (ctDNA) tests have revolutionized clinical management of LC patients, their effectiveness is restricted in settings with lower tumor burden, molecular heterogeneity, and bias in sampling approaches. In this scenario, the epigenetic profiling of cell-free DNA (cfDNA) stands out as a promising, less invasive approach, accurately detect cancer traces. Evidence from stage I-II disease and CT-detected pulmonary nodules supports the diagnostic potential of cfDNA methylation, although further validation in prospective screening cohorts remains necessary. Beyond genomic alterations, cfDNA epigenetic changes, including DNA methylation, chromatin organization, nucleosome positioning, and fragmentation patterns, reflect multi-dimensional complexity of tumor biology. These properties convey both the functional status and the origin of the circulating DNA fragments, accelerating for tumor integrating genomic analysis. Within this group, DNA methylation is the biologically robust and clinically well-established epigenetic marker, as alterations in methylation linked to cancer often occur in the early stages of tumorigenesis and are commonly found across different cancer cell types. Here, we explored the biological and clinical relevance of the epigenetic landscape of cfDNA in LC patients, particularly focusing on DNA methylation-based biomarkers and their evolving applications towards early diagnosis and post-surgical monitoring of minimal residual disease (MRD). We aimed to comprehensively overview analytical approaches for cfDNA methylation analysis, including targeted and genome-wide profiling strategies, and discuss their integration with machine learning (ML) and multi-omics frameworks in order to improve diagnostic performance and clinical applicability in LC management.

DNA methylation↗

PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗

PubMed1998

Transgene-promoted epigenetic switches of chalcone synthase activity in petunia plants.

Epigenetic variation affecting pigment pattern formation in petunia flowers due to the insertion of transgenes encoding chalcone synthase is described. The loss of pigment formation in petals or parts of petals is due to the post-transcriptional degradation of chalcone synthase RNA, from both the endogenous petunia chalcone synthase genes and from the chalcone synthase transgenes. The RNA cleavage pathway and its control are described. Different epigenetic states of RNA breakdown are correlated with specific cytosine methylation changes in the coding sequences of the genes. The probability, extent and developmental location of chalcone synthase RNA breakdown are related to the number and organization of transgenes in the genome but epigenetic switches that affect RNA turnover probably occur in meristems and between sexual generations. Hypotheses to explain how the transgenes influence the levels of chalcone synthase RNA breakdown and how different epigenetic states are created are discussed.

Acyltransferases↗

PubMed2006

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth.

Human chromosome 11p15 comprises two imprinted domains important in the control of fetal and postnatal growth. Novel studies establish that imprinting at one of these, the IGF2-H19 domain, is epigenetically deregulated (with loss of DNA methylation) in Silver-Russell Syndrome (SRS), a congenital disease of growth retardation and asymmetry. Previously, the exact opposite epigenetic alteration (gain of DNA methylation) had been detected at the domain's 'imprinting control region' (ICR) in patients with Beckwith-Wiedemann Syndrome (BWS), a complex disorder of fetal overgrowth. However, more frequently, BWS is caused by loss of DNA methylation at the ICR that regulates the second imprinted domain at 11p15. Interestingly, a similar epigenetic alteration (with loss of methylation) at a putative ICR on human chromosome 6q24, is involved in transient neonatal diabetes mellitus (TNDM), a congenital disease with intrauterine growth retardation and a transient lack of insulin. Thus, fetal and postnatal growth is epigenetically controlled by different ICRs, at 11p15 and other chromosomal regions.

Beckwith-Wiedemann Syndrome↗

PubMed2002

Genomic imprinting and epigenetic reprogramming: unearthing the garden of forking paths.

Genomic imprinting, an epigenetic form of gene regulation, determines the parent-dependent gene expression of marked or imprinted genes during gametogenesis and embryonic development. Imprinting involves differential allele DNA methylation in one sex cell lineage but not in the other. Egg and sperm each contributes the same DNA sequences to the zygote but epigenetic imprinting of a subset of genes determines that only one of the parent alleles are expressed relative to the parental origin. Primordial germ cells inherit biallelically imprinted genes from maternal and paternal origin and erase their imprints to start de novo monoallelic imprinting during gametogenesis. Epigenetic paternalization is an ongoing process in the mitotically-dividing spermatogonial stem cell and derived meiotically-dividing spermatocyte progeny to endow sperm with imprinted alleles. Epigenetic maternalization is restricted to the oocyte growth phase of folliculogenesis and is unrelated to DNA replication since it takes place while the oocyte remains in the diplotene stage of meiotic prophase I. Sperm and oocyte genomic methylation patterns depend on the activity of DNA methyltransferases (Dnmt). A variant of Dnmt1, designated Dnmt1o, accumulates in oocyte nuclei during the follicular growth phase. Dnmt3L, an isoform of Dnmt3a and Dnmt3b, but lacking enzymatic activity, interacts with Dnmt2a and Dnmt3b and is required for spermatogenesis. In the mouse early zygote, the male pronucleus is demethylated within 4 h of fertilization. Global demethylation takes place gradually up to the morula stage. In the blastocyst, de novo methylation is reestablished in the inner cell mass but not in the trophectoderm. Both the significance of genomic imprinting and the severe developmental defects caused by disrupted Dnmt activity, point to a need for a better understanding of the causes of low cloning efficiency by somatic nuclear transfer to enucleated ovulated oocyte.

Animals↗

PubMed2025

Nanoscale Epigenetic Profiling of Colorectal Cancer Cell-Derived Exosomes via Single-Vesicle Nanoscopy.

Exosomes play critical roles in cancer diagnosis and treatment as they carry molecular information that reflects the epigenetic state of their parent cells. For the first time, nanoscale epigenetic profiling of individual exosomes derived from colorectal cancer cell lines is demonstrated via photo-induced force microscopy (PiFM). Exosomes from three cell lines with distinct CpG island methylator phenotype (CIMP) status are analyzed at the single-vesicle level. The nano-IR method provides simultaneous high-resolution topographical and spectroscopic data, revealing detailed vibrational signatures that distinguish CIMP-high (HCT116 and HT29) exosomes from CIMP-negative (SW480) ones. Notably, exosomes from CIMP-high cells exhibit red-shifted amide I and nucleic acid region compared to those from CIMP-negative cells, a shift attributed to increased 5-methylcytosine (5mC) modifications, as verified by quantum chemical calculations. Furthermore, these measurements reveal heterogeneity among individual exosomes, suggesting the presence of distinct subpopulations with unique epigenetic profiles, demonstrating the importance of single-vesicle resolution to detect molecular variations that remain obscured in ensemble studies. These findings present the potential of PiFM-based single-vesicle analysis to identify epigenetic markers in exosomes, laying the groundwork for its application in refined cancer diagnostics and targeted therapeutic strategies.

Humans↗

PubMed1994

Specifying epigenetic states with autoregulatory transcription factors.

Epigenetic information, not DNA sequence, distinguishes different cell types within a multicellular organism. The molecular nature of epigenetic information specifying differentiated cell types is unknown. However, it must be stable over time and mitotically heritable. In this paper, steady-state levels of autoregulatory transcription factors are explored as a potential form of epigenetic information. In particular, a model autoregulatory transcription factor having two alternative stable steady-state levels is presented. Each steady-state level specifies a phenotypically distinguishable epigenetic state, analogous to a differentiated cell type. These states are mitotically stable if the transcription factor is inherited during cell division.

Animals↗

PubMed2005

The epigenetic breakdown of cancer cells: from DNA methylation to histone modifications.

The recognition of epigenetic defects in all types of cancer has represented a revolutionary achievement in cancer research in recent years. DNA methylation aberrant changes (global hypomethylation and CpG island hypermethylation) were among the first events to be recognized. The overall scenario comprises a network of factors in which deregulation of DNA methyltransferases leads to a cancer-type specific profile of tumor suppressor genes that become epigenetically silenced. Over recent years, a better understanding of the machinery that connects DNA methylation, chromatin and transcriptional activity, in which histone modifications stand in a key position, has been achieved. The identification of these connections has contributed not only to understanding how epigenetic deregulation occurs in cancer but also to developing novel therapies that can reverse epigenetic defects in cancer cells.

DNA (Cytosine-5-)-Methyltransferase 1↗

PubMed2005

Epigenetic regulation of mammalian imprinted genes: from primary to functional imprints.

Parental genomic imprinting was discovered in mammals some 20 years ago. This phenomenon, crucial for normal development, rapidly became a key to understanding epigenetic regulation of mammalian gene expression. In this chapter we present a general overview of the field and describe in detail the 'imprinting cycle'. We provide selected examples that recapitulate our current knowledge of epigenetic regulation at imprinted loci. These epigenetic mechanisms lead to the stable repression of imprinted genes on one parental allele by interfering with 'formatting' for gene expression that usually occurs on expressed alleles. From this perspective, genomic imprinting remarkably illustrates the complexity of the epigenetic mechanisms involved in the control of gene expression in mammals.

Animals↗

PubMed2006

The role of histone modifications in epigenetic transitions during normal and perturbed development.

Epigenetic mechanisms control eukaryotic development beyond DNA-stored information. DNA methylation, histone modifications and variants, nucleosome remodeling and noncoding RNAs all contribute to the dynamic make-up of chromatin under distinct developmental options. In particular, the great diversity of covalent histone tail modifications has been proposed to be ideally suited for imparting epigenetic information. While most of the histone tail modifications represent transient marks at transcriptionally permissive chromatin, some modifications appear more robust at silent chromatin regions, where they index repressive epigenetic states with functions also outside transcriptional regulation. Under-representation of repressive histone marks could be indicative of epigenetic plasticity in stem, young and tumor cells, while committed and senescent (old) cells often display increased levels of these more stable modifications. Here, we discuss profiles of normal and aberrant histone lysine methylation patterns, as they occur during the transition of an embryonic to a differentiated cell or in controlled self-renewal vs pro-neoplastic or metastatic conditions. Elucidating these histone modification patterns promises to have important implications for novel advances in stem cell research, nuclear reprogramming and cancer, and may offer novel targets for the combat of tumor cells, potentially leading to new diagnostic and therapeutic avenues in human biology and disease.

Animals↗

PubMedDate not supplied

Linear genetics, non-linear epigenetics: complementary approaches to understanding complex diseases.

Recent discoveries and rediscoveries in molecular and cell biology, in population and evolutionary biology, and in disease natural history raise new doubts about the ability of genetic analysis alone to predict multifactorial (polygenic) human diseases and other complex phenotypes. These doubts serve to redirect our attention to epigenetic regulation as a second informational system in parallel with the genome. Epigenetic regulation is now viewed by many biologists as a process that includes mechanisms capable of constraining the genome and providing for new patterns of gene expression. Epigenetic networks, both intra- and inter-cellular, provide a basis for nonlinear and chaotic views of cellular and tissue level differentiation and organization, and thus provide a more dynamic approach to understanding the creation of complex phenotypes, even from isogeneic conditions. The reality of regulatory networks within cells inserted, as it were, between genome and phenome, also helps explain the difficulties now encountered when prediction and diagnosis of complex disease omits epigenetic considerations and depends entirely on gene causality.

Animals↗