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At least 307 records · Page 17Linked to original sources

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

Epigenetic clues: Predicting maternal depression through DNA methylation.

Perinatal depression (PND) is a prevalent and multifactorial mood disorder affecting approximately 10-20 % of women globally, with higher burdens reported in low- and middle-income countries. Despite the availability of screening tools such as the Edinburgh Postnatal Depression Scale, these approaches primarily identify risk without elucidating underlying biological mechanisms. Emerging evidence highlights the role of epigenetic regulation particularly DNA methylation as a key mediator linking genetic susceptibility and environmental exposures during the perinatal period. This review synthesizes current knowledge on DNA methylation dynamics in maternal depression, emphasizing both candidate gene and epigenome-wide association study (EWAS) approaches. Candidate gene studies have identified differential methylation in stress-related pathways, including HPA axis genes (NR3C1, FKBP5), serotonergic signalling (SLC6A4), and oxytocin pathways (OXTR), though findings remain limited by poor reproducibility and small sample sizes. In contrast, EWAS provides a hypothesis-free framework, identifying novel differentially methylated positions and regions associated with PND, including predictive CpG panels with potential diagnostic utility. The review also highlights the importance of tissue specificity, temporal epigenetic remodeling across pregnancy, and the interplay between maternal and fetal epigenomes. Furthermore, methodological challenges such as heterogeneity in study design, lack of replication, and analytical inconsistencies remain barriers to clinical translation. Integrating genetic, epigenetic, and environmental data through multi-omics approaches may enhance predictive accuracy and improve early intervention strategies. Overall, DNA methylation represents a promising avenue for understanding the biological underpinnings of PND and developing robust biomarkers for risk prediction and personalized care.

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

How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.

Neurodegenerative diseases are increasingly recognized as disorders involving immune dysregulation. However, the mechanisms underlying this dysfunction remain poorly characterized. Trained immunity has recently emerged as a potential contributor to immune dysregulation, particularly in neuroinflammation and neurodegenerative diseases, where trained immunity is the epigenetic reprogramming of innate immune responses following an initial inflammatory stimulus, which increases responses to subsequent exposures. In parallel, although the brain has traditionally been viewed as an immune-privileged organ, growing evidence indicates that peripheral immune activity exerts significant influence on neuroinflammation in the brain. A major driver of peripheral immunity is the microbiome. Therefore, this perspective aims to present a conceptual framework for a relationship between the microbiome, trained immunity, and neurodegenerative diseases. We first summarize evidence of trained immunity in the brain and its role in neurodegeneration. Next, we highlight the role of the microbiome in peripheral immune modulation and in trained immunity. Finally, we propose potential mechanisms through which the microbiome may induce or modulate trained immunity in the brain. These include: 1) immunogenic microbial metabolites that cross the blood-brain barrier and alter host cell epigenetics; 2) migration of peripherally trained myeloid cells into the brain; 3) viral infection-induced trained immunity that may predispose to neurodegeneration. Together, this perspective suggests that microbiome-induced trained immunity offers a novel mechanism linking peripheral immune regulation with neuroinflammation and neurodegeneration with implications for therapeutic targeting of epigenetic modification as a molecular prevention strategy for progression of neurodegeneration.

Humans↗

PubMed2026

Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.

Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.

Humans↗

PubMed2024

Multilevel Proteomics Reveals Epigenetic Signatures in BCG-Mediated Macrophage Activation.

The bacillus Calmette-Guérin BCG vaccine (Mycobacterium bovis) is primarily used to prevent tuberculosis (TB) infections but has wide-ranging immunogenic effects. One of its most notable properties is its ability to induce trained immunity, a memory-like response in innate immune cells such as macrophages. Through targeted analyses of well-established histone marks, prior research has shown that these changes are generated through epigenetic modification. Mass spectrometry-based proteomic approaches provide a way to globally profile various aspects of the proteome, providing data to further identify unexplored mechanisms of BCG-mediated immunomodulation. Here we use multi-level proteomics (total, histone, and phospho to identify networks and potential mechanisms that mediate BCG-induced immunomodulation in macrophages. Histone-focused proteomics and total proteomics were performed at the University of Cape Town (data available via ProteomeXchange with identifier PXD051187), while phosphoproteomics data was retrieved from the ProteomeXchange Repository (identifier PXD013171). We identify several epigenetic mechanisms that may drive BCG-induced training phenotypes. Evidence across the proteomics and histone-focused proteomics data set pair 6 epigenetic effectors (NuA4, NuRD, NSL, Sin3A, SIRT2, SIRT6) and their substrates.

Epigenesis, Genetic↗

PubMed2025

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Autophagy↗

PubMed2026

DNA methylation-based ageing in a deuterostome invertebrate: an epigenetic clock for the crown-of-thorns seastar (Acanthaster cf. solaris).

Accurate and reliable ageing tools are essential for wildlife conservation and management. While DNA methylation has emerged as a promising tool for age estimation in vertebrates, its application to invertebrates remains contested and has been limited to arthropods. Here, we develop an epigenetic clock for the Pacific crown-of-thorns seastar (CoTS; Acanthaster cf. solaris), a destructive coral predator contributing to habitat degradation across Indo-Pacific reefs. Using Oxford Nanopore Technologies, we generated whole-genome DNA methylation profiles across five age groups and identified 1910 CpG sites with methylation patterns significantly associated with age. We then fitted age prediction models using elastic net regression and evaluated predictive performance with leave-one-out cross-validation (LOOCV), achieving a mean absolute error of 0.31 ± 0.22 years, corresponding to 4-6% of the CoTS lifespan (5-8 years). This accuracy suggests the potential to differentiate annual cohorts, supporting future management-relevant inference. To facilitate practical implementation, we constructed an optimized epigenetic clock from 14 CpG sites consistently selected across LOOCV iterations. Our results demonstrate that DNA methylation-based age estimation is feasible in a deuterostome invertebrate, extending epigenetic ageing approaches beyond arthropods and establishing their potential to advance age determination and management in invertebrates that lack reliable ageing methods.

Animals↗

PubMed2026

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Aging↗

PubMed2026

Sex-specific differences in liver DNA methylation patterns and epigenetic aging in mice.

Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This study investigated whether aged male and female mice display distinct liver DNA methylation patterns and differences in epigenetic aging. Liver samples were collected from 17 aged c57BL/6 mice (6 males, 11 females). Genomic DNA was extracted and bisulfite-converted before targeted enrichment of 2,045 murine age-associated CpG loci. Biological age (DNAge) was estimated using a previously developed DNA methylation-based predictor generated through elastic net regression. The difference (ΔDNAge) between DNAge and chronological age was computed. Sex-specific differences were assessed by comparing site-specific methylation ratios, ΔDNAge values, and through principal component analysis (PCA) and multiple linear regression. Twelve CpG sites across six genes (Fam84b, Zswim6, Hsf4, Mn1, Qprt, and Rapgefl1) showed significant sex-associated differences in methylation. Fam84b demonstrated the largest and most consistent sex-associated effect, with all three associated CpG sites showing higher methylation in males (regression coefficients: -0.204, -0.281, and -0.294). Zswim6 exhibited consistent lower methylation ratios in females, whereas the other genes showed higher methylation in females. There were no sex differences in biological age or ΔDNAge (P = 0.596). Although the epigenetic clock did not reveal differences between sexes in aging, aged mice did exhibit sex-specific liver methylation patterns different from those reported in younger mice, suggesting that sex-dependent epigenetic changes may emerge later in life and may reflect sexual dimorphism in liver function with age.NEW & NOTEWORTHY Males and females are known to age differently and develop certain diseases at different rates. Here, we examined the livers of aged male and female mice to see if they show different DNA methylation patterns. We found that aged male and female mice had distinct DNA methylation patterns at specific genes. Interestingly, most of these methylation differences were not present in younger mice, suggesting that sex differences in the genome may change with age.

Animals↗

PubMed2026

Epigenetic safety of in vitro maturation in PCOS: genome-wide DNA methylation profiling of cord blood from a randomized controlled trial.

BACKGROUND: In vitro maturation (IVM) provides a safer alternative to conventional in vitro fertilization (IVF) for women with polycystic ovary syndrome (PCOS) by mitigating the risk of ovarian hyperstimulation. However, concerns persist regarding whether IVM perturbs epigenetic reprogramming in the offspring. Current evidence is constrained by candidate-gene approaches or a lack of parental controls. This study aimed to evaluate the genome-wide DNA methylation safety of IVM compared with conventional IVF using a rigorous trio-based design. METHODS: This secondary epigenetic analysis was nested within a randomized controlled trial (RCT) (ClinicalTrials.gov: NCT03463772). We included 10 nuclear families (trios), comprising five IVM-conceived and five IVF-conceived singleton offspring alongside their biological parents. Both groups utilized a uniform freeze-only single-blastocyst transfer strategy to minimize hormonal confounding. Genomic DNA from umbilical cord blood (UCB) and parental peripheral blood was analyzed using reduced representation bisulfite sequencing (RRBS). Genome-wide methylation patterns and differentially methylated regions (DMRs) were subsequently compared between the groups. RESULTS: Clinical characteristics were comparable between the IVM and IVF groups. Genome-wide analyses demonstrated high concordance in UCB methylation patterns, revealing no significant differences in global CpG methylation levels or distributions across key genomic features (promoters, CpG islands, and gene bodies). Only three rare DMRs were identified in UCB (representing ~ 0.0001% of the genome), none of which mapped to imprinted or developmentally critical loci. Furthermore, methylation variability remained consistent between the groups. CONCLUSIONS: Our findings provide robust mechanistic evidence supporting the epigenetic safety of IVM. The remarkable stability of the neonatal methylome confirms that specific IVM conditions do not compromise early developmental programming, thereby endorsing IVM as a safe and viable alternative for women with PCOS. TRIAL REGISTRATION: ClinicalTrials.gov registry, NCT03463772. Registered on March 13, 2018.

Humans↗

PubMed2026

Multi-omics integration uncovers epigenetic control of metabolic reprogramming in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, limiting effective targeted therapies. Increasing evidence suggests that metabolic reprogramming, a hallmark of TNBC progression, is driven by underlying epigenetic mechanisms such as DNA methylation. The represented study performed an integrative analysis of transcriptomic (RNA-seq) and methylome data to uncover the metabolic-epigenetic interplay in TNBC. Differential gene expression analysis using DESeq2 revealed significant dysregulation of key metabolic genes, including upregulation of genes encoding glycolytic and serine biosynthesis enzymes and downregulation of metabolic tumor suppressors. Genome-wide methylation profiling identified extensive cytosine-phosphate-guanine (CpG) hypermethylation events associated with transcriptional repression, particularly in promoter regions. Integrative analysis pinpointed a subset of metabolism-related genes exhibiting both differential expression and methylation, such as FBP1, RASSF1A, and PHGDH. Pathway enrichment analysis highlighted aberrations in glycolysis/gluconeogenesis, fatty acid metabolism, and one-carbon pathways (adjusted p < 0.01). Importantly, TNBC patients with hypermethylated metabolic gene signatures displayed significantly shorter overall survival (log-rank p < 0.05). These findings reveal that DNA methylation-driven metabolic dysregulation contributes to TNBC aggressiveness and may provide novel biomarkers and therapeutic targets at the metabolic-epigenetic interface.

Humans↗

PubMed2026

Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.

Childhood obesity is a complex disorder which results from the combined contribution of genetics, the environment, and development, which is programmed and coordinated by epigenetic mechanisms. Of them, DNA methylation has emerged as an important molecular interface between environmental inputs and changes in gene expression. In this review, we provide an overview of the role of DNA methylation in childhood obesity during the key developmental stages, from prenatal life and childhood to adolescence. We also highlight the available evidence from candidate genes and genome-wide association studies implicating critical loci involved in energy homeostasis and adipogenesis, where DNA methylation is altered. Further, we also provide an overview of how maternal obesity, nutritional status, and bariatric surgery shape offspring's methylation profiles and contribute to the increased risk of programming obesity across generations. Although aberrant methylation patterns are consistently associated with altered metabolic phenotypes, disentangling causality remains a significant challenge. Herein, we highlight emerging approaches, such as rigorous longitudinal cohorts, epigenetic Mendelian randomization, and CRISPR-based epigenome editing, that are beginning to provide the analytical clarity needed to move beyond association. Finally, we examine the potential of DNA methylation signatures to inform early risk stratification and prevention possibilities. Although yet to be clinically validated, whole-genome methylation profiling is increasingly integrated with systems biology and multi-omics frameworks, making the identification of robust, clinically actionable markers more promising. A more precise understanding of how epigenetic processes shape susceptibility to childhood obesity could ultimately support strategies capable of altering lifelong metabolic trajectories.

Humans↗

PubMed1996

A possible role in chemical carcinogenesis for epigenetic, heritable changes in gene expression.

Although genetic changes are clearly important in the initiation of carcinogenesis, there is reason to think that epigenetic changes may also play a role in the process. A key feature of carcinogenesis is the long latency between exposure to carcinogenic insults and the appearance of malignancy. Thus, if epigenetic changes are to be involved, they must somehow be inherited at each cell division without the continued presence of the carcinogen. I propose that self-perpetuating changes in patterns of gene expression are a plausible mechanism for an epigenetic component of carcinogenesis. Networks of transcription factors that regulate each other's and their own expression are known to control important developmental processes, particularly the determination of entire cell lineages. An inherent property of many such autoregulatory networks is the existence of two very distinct, stable steady-states, defined in terms of the concentration of each transcription factor in the network. In this report, I present a model in which an acute carcinogen exposure is postulated to shift such a network from one steady-state to the other, effectively turning on or off the expression of at least one of the genes. Because of the autoregulatory nature of the network, this new steady-state is stably inherited at each cell division. Such changes in gene expression may ultimately contribute to the malignant phenotype if the regulatory network affects genes important in cell-cycle checkpoints, maintenance of genome stability, signal transduction, or other processes that are altered in tumor cells.

Animals↗

PubMed2000

Histone acetylation and an epigenetic code.

The enzyme-catalyzed acetylation of the N-terminal tail domains of core histones provides a rich potential source of epigenetic information. This may be used both to mediate transient changes in transcription, through modification of promoter-proximal nucleosomes, and for the longer-term maintenance and modulation of patterns of gene expression. The latter may be achieved by setting specific patterns of histone acetylation, perhaps involving acetylation of particular lysine residues, across relatively large chromatin domains. The histone acetylating and deacetylating enzymes (HATs and HDACs, respectively) can be targeted to specific regions of the genome and show varying degrees of substrate specificity, properties that are consistent with a role in maintaining a dynamic, acetylation-based epigenetic code. The code may be read (ie. exert a functional effect) either through non-histone proteins that bind in an acetylation-dependent manner, or through direct effects on chromatin structure. Recent evidence raises the interesting possibility that an acetylation-based code may operate through both mitosis and meiosis, providing a possible mechanism for germ-line transmission of epigenetic changes.

Acetylation↗

PubMed1998

Epigenetic mechanisms in the regulation of the maize Suppressor-mutator transposon.

Transcription and transposition of the maize Suppressor-mutator (Spm) transposon are epigenetically controlled. Methylation of specific element sequences prevents transcription and transposition in a heritable manner. Reactivation and demethylation occur in the presence of an active element, implying the existence of an element-encoded epigenetic activator. The methylation target sequences are the 0.2 kb promoter and an 0.35 kb GC-rich downstream sequence. Two Spm-encoded proteins, TnpA and TnpD, participate in transposition. In addition, TnpA has positive and negative regulatory activities. TnpA represses and activates the unmethylated and methylated Spm promoters, respectively, and it participates in the transient and heritable demethylation of the promoter and GC-rich region. There is evidence that TnpA-mediated repressor and epigenetic activator functions occur by different molecular mechanisms.

DNA Transposable Elements↗

PubMed2005

Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.

The treatment of cancer through the development of new therapies is one of the most important challenges of our time. The decoding of the human genome has yielded important insights into the molecular basis of physical disorders, and in most cases a connection between failures in specific genes and the resulting clinical symptoms can be made. The modulation of epigenetic mechanisms enables, by definition, the alteration of cellular phenotype without altering the genotype. The information content of a single gene can be crucial or harmful, but the prerequisite for a cellular effect is active gene transcription. To this end, epigenetic mechanisms play a very important role, and the transcription of a given gene is directly influenced by the modification pattern of the surrounding histone proteins as well as the methylation pattern of the DNA. These processes are effected by different enzymes which can be directly influenced through the development of specific modulators. Of course, all genetic information is written as a four-character code in DNA. However, epigenetics describes the art of reading between the lines.

Acetylation↗

PubMed2024

A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis.

OBJECTIVE: Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study. METHODS: We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. RESULTS: This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development. CONCLUSION: Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Humans↗