The glucocorticoid receptor (GR) is a critical nuclear receptor that regulates gene expression in diverse tissues, including the heart, where it plays a key role in maintaining cardiovascular health. GR signaling influences essential processes within cardiomyocytes, including hypertrophy, calcium handling, and metabolic balance, all of which are vital for proper cardiac function. Dysregulation of GR activity has been implicated in various cardiovascular diseases (CVDs), highlighting the potential of GR as a therapeutic target. Remarkably, recent insights into GR's epigenetic regulation and its interaction with circadian rhythms reveal opportunities to optimize therapeutic strategies by aligning glucocorticoid administration with circadian timing. In this review, we provide an overview of the glucocorticoid receptor's role in cardiac physiology, detailing its genomic and non-genomic pathways, interactions with epigenetic and circadian regulatory mechanisms, and implications for cardiovascular disease. By dissecting these molecular interactions, this review outlines the potential of epigenetically informed and circadian-timed interventions that could change the current paradigms of CVD treatments in favor of precise and effective therapies.

Mycobacterium tuberculosis (MTB) uses epigenetics to avoid the hostile host immune defence systems and also mount resistance to chemotherapy when exposed to antibiotic stress. MTB's epigenetic survival tool-kit includes genomic DNA histone acetylation/deacetylation, methylation, phosphorylation, ubiquitylation, etc. The non-coding host microRNAs (miRNAs) as genomic products of epigenetic control of drug extrusion processes, drug permeability barrier formation or metabolism, and target alteration are hijacked by MTB to mount multi-drug resistance. The miRNAs involved and the mechanisms used are not yet completely understood. The role of MTB genome-derived miRNA are currently indeterminate as the current studies are only focused on the host miRNA biogenesis in MTB pathogenesis. However, the contribution of host miRNA to drug resistance in MTB chemotherapy is largely unknown.

We have comprehensively searched online databases for medical, health, and nanotechnology for articles published in English between 2020 and 2024 using search words "MTB", "Epigenetics", "microRNA", "TB Chemotherapy" to compile this narrative review.

MTB epigenetic tool-kit of DNA methylation, histone acetylation/deacetylation, cell membrane impermeability, drug metabolism and target mimicry are mediated by the hijacked host cell microRNAs in the development of drug resistance. Antisense oligomers or mimetics can therefore, be used as miRNA antagonists/silencers or agomirs, respectively, depending on the pattern of miRNA expression, to combat resistance to MTB chemotherapy.

This review discusses microRNAs as epigenetic agents in the emergence of Multi-Drug Resistance TB (MDR-TB) and their potential role in chemotherapeutics.

Glucocorticoids (GCs) are widely used anti-inflammatory agents that inhibit growth in children. However, their mechanisms and effect on the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis remain unclear.

This study, we aimed to establish a mouse model of GC-induced growth retardation during the critical growth period and explore the underlying mechanisms. Additionally, we aimed to identify novel biomarkers and potential therapeutic agents for GC-induced growth impairment.

Four-week-old mice were treated with GCs for two weeks and subsequently assessed for body length, weight, and body composition. Immunohistochemical analysis of the growth plate in the proximal tibia and biochemical assays of blood were performed to evaluate changes in growth plate length and GH/IGF-1 axis. KMT1A expression and its effects on Ghr expression were examined, and the impact of berberine on GC-induced growth retardation was assessed.

GCs significantly reduced growth by impairing growth plate expansion, disrupting the GH/IGF-1 axis, and downregulation of the GH receptor (Ghr) and Igf-1 levels in the liver. These changes were attributed to the upregulation of the H3K9 trimethyltransferase KMT1A, which decreased Ghr transcription in the liver. In vitro screening of natural compounds revealed that berberine chloride hydrate decreased the KMT1A levels and increased GHR levels. Berberine chloride hydrate also effectively ameliorated GC-induced growth retardation by restoring Ghr expression via KMT1A inhibition, thereby enhancing the circulating IGF-1 levels.

Overall, our findings highlight the potential of targeting KMT1A using berberine chloride hydrate as an epigenetic modifier to treat GC-induced growth impairment.

Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

The convergence of artificial intelligence (AI) and biomedical data is transforming precision medicine by enabling the use of genetic risk factors (GRFs) for customized healthcare services based on individual needs. Although GRFs play an essential role in disease susceptibility, progression, and therapeutic outcomes, a gap exists in exploring their contribution to AI-powered precision medicine. This paper addresses this need by investigating the significance and potential of utilizing GRFs with AI in the medical field. We examine their applications, particularly emphasizing their impact on disease prediction, treatment personalization, and overall healthcare improvement. This review explores the application of AI algorithms to optimize the use of GRFs, aiming to advance precision medicine in disease screening, patient stratification, drug discovery, and understanding disease mechanisms. Through a variety of case studies and examples, we demonstrate the potential of incorporating GRFs facilitated by AI into medical practice, resulting in more precise diagnoses, targeted therapies, and improved patient outcomes. This review underscores the potential of GRFs, empowered by AI, to enhance precision medicine by improving diagnostic accuracy, treatment precision, and individualized healthcare solutions.

Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.

Alternative splicing enables a single precursor mRNA to generate multiple mRNA isoforms, leading to protein variants with different structures and functions. Abnormal alternative splicing is frequently associated with cancer development and progression. Recent studies have revealed a complex and dynamic interplay between epigenetic modifications and alternative splicing. On the one hand, dysregulated epigenetic changes can alter splicing patterns; on the other hand, splicing events can influence epigenetic landscapes. The reversibility of epigenetic modifications makes epigenetic drugs, both approved and investigational, attractive therapeutic options. This review provides a comprehensive overview of the bidirectional relationship between epigenetic regulation and alternative splicing in cancer. It also highlights emerging therapeutic approaches aimed at correcting splicing abnormalities, with a special focus on drug-based strategies. These include epigenetic inhibitors, antisense oligonucleotides (ASOs), small-molecule compounds, CRISPR-Cas9 genome editing, and the SMaRT (splice-switching molecule) technology. By integrating recent advances in research and therapeutic strategies, this review provides novel insights into the molecular mechanisms of cancer and supports the development of more precise and effective therapies targeting aberrant splicing.

Recent advances in screening programs and the development of innovative therapeutic strategies have significantly improved the clinical outcomes of cancer patients. However, many patients still experience treatment failure, primarily due to inherent or acquired drug resistance mechanisms. This challenge underscores the urgent need for novel therapeutic targets for the effective treatment of malignancies, as well as cancer-specific biomarkers to enhance early diagnosis and guide interventions. Epigenetic mechanisms, including DNA methylation, have recently garnered growing interest as key regulators of gene expression under both physiological and pathological conditions. Although epigenetic dysregulations are reliable tumor hallmarks, DNA methylation is still not routinely integrated into clinical practice, highlighting the need for further research to translate preclinical findings from the bench to the bedside. On these bases, the present review aims to illustrate the state of the art regarding the role of DNA methylation in cancer, describing the technologies currently available for DNA methylation profiling. Furthermore, the latest evidence on the application of DNA methylation hotspots in cancer diagnosis and prognosis, as well as the impact of epidrugs in cancer care, is discussed to provide a comprehensive overview of the potential clinical relevance of DNA methylation in advancing personalized medicine.

Aging is a physiological process that culminates in cellular senescence, a phenomenon that has significant implications for health and longevity. Plant-based therapeutics, particularly the root of Withania somnifera, have been reported to delay the onset and progression of aging and its associated disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the role of leaf-derived microRNAs (miRNAs) from W. somnifera in the molecular regulation of genes involved in aging remains poorly understood. Caenorhabditis elegans serves as an indispensable model organism for studying aging-associated gene regulation due to its short lifespan, conserved human orthologs, and ease of laboratory cultivation. In this study, we explored the regulatory interactions between miRNAs derived from the leaf tissues of W. somnifera and aging-associated genes, utilizing C. elegans as a model organism. We employed bioinformatics to identify miRNAs that interact with aging-associated genes in C. elegans and found that three specific miRNAs in the leaf tissue of W. somnifera interacted with these genes. To assess the physiological effects of these miRNAs on C. elegans, we conducted biochemical assays, including lifespan, chemotaxis, and stress resistance assays. Additionally, we investigated the differential gene expression of the interacting genes in the presence and absence of W. somnifera leaf miRNA treatment using real-time PCR. The results indicated that the expression levels of the age-1 and sel-12 genes were significantly downregulated, while the apl-1 gene was upregulated following treatment with leaf miRNAs in C. elegans. These findings suggest that miRNAs derived from W. somnifera leaves may play a crucial role in regulating aging-associated gene expression. This is the first study, to our knowledge, that identifies the miRNAs of W. somnifera leaf involved in aging-associated gene regulation, thereby paving the way for future research into the therapeutic potential of plant-derived miRNAs in combating age-related disorders.

Epigenetic mechanisms, including DNA methylation, histone modifications, and Noncoding RNAs, play a critical role in enabling plants to adapt to environmental changes without altering their DNA sequence. These processes dynamically regulate gene expression in response to diverse stressors, making them essential for plant resilience under changing global conditions. This review synthesises research on tropical and subtropical plants-species naturally exposed to extreme temperatures, salinity, drought, and other stressors-while drawing parallels with similar mechanisms observed in arid and temperate ecosystems. By integrating molecular biology with plant ecology, this synthesis highlights how tropical plants provide valuable models for understanding resilience strategies applicable across broader plant taxa. This review underscores the potential of epigenetic mechanisms to inform conservation strategies and agricultural innovations aimed at bolstering plant resilience in the face of climate change.

Psychosocial factors, including cumulative psychosocial stress and loneliness, have been linked to epigenetic aging in older adults. Further, depressive symptoms have established relationships with both psychosocial factors and epigenetic aging. However, it is not known whether depressive symptoms mediate the association between psychosocial factors and epigenetic aging.We conducted linear regression models to examine associations between psychosocial stress, loneliness, and depressive symptoms and five epigenetic age acceleration (AA) measures estimated by DNA methylation in a multi-racial/ethnic sample of 2681 older adults from the Health and Retirement Study (mean age: 70.4 years). For all identified associations, we tested for effect modification by sex and educational attainment and performed mediation analysis to characterize the role of depressive symptoms on these associations.Psychosocial stress, loneliness, and depressive symptoms were each associated with at least one measure of epigenetic AA (FDR q < 0.05). Further, we observed interactions between loneliness, psychosocial stress, and sex on DunedinPACE, as well as loneliness and educational attainment on GrimAA, PhenoAA, and DunedinPACE, with females and individuals without a college degree appearing more sensitive to the psychosocial effects on epigenetic aging. Depressive symptoms mediated between 24 % and 35 % of the relationships between psychosocial stress and HannumAA, GrimAA, and DunedinPACE, as well as 40 % and 37 % of the relationships between loneliness and both GrimAA and DunedinPACE, respectively.

from this study may help elucidate the relationship between psychosocial factors and epigenetic aging, which is critical in understanding the biological mechanisms through which psychosocial factors may contribute to age-related disease.

YEATS2, an evolutionarily conserved reader of histone acylation marks (H3K27ac, H3K27cr, H3K27bz), functions as a central oncogenic driver in diverse cancers, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Its structurally plastic YEATS domain bridges acyl-CoA metabolism to chromatin remodeling, amplifying transcription of survival genes such as MYC, BCL2, and PD-L1. YEATS2 orchestrates malignancy-specific programs-sustaining ribosome biogenesis in NSCLC through ATAC complex recruitment, enhancing NF-κB-dependent immune evasion in PDAC, and activating PI3K/AKT-driven metabolic rewiring in HCC. Structural studies demonstrate a unique aromatic cage architecture that selectively engages diverse acylated histones. Although pyrazolopyridine-based inhibitors targeting the YEATS domain show preclinical efficacy, developing isoform-selective agents remains challenging. Clinically, YEATS2 overexpression correlates with therapy resistance and may synergize with immune checkpoint blockade. This review integrates mechanistic insights into the role of YEATS2 in epigenetic regulation, evaluates its therapeutic potential, and proposes future directions: elucidating full-length complex topologies, mapping synthetic lethal interactors, and optimizing selective inhibitors. Disrupting YEATS2-mediated epigenetic adaptation presents novel opportunities for precision cancer therapy.

Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme's active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy.

Methionine, an essential sulfur-containing amino acid, plays a critical role in methyl metabolism, folate metabolism, polyamine synthesis, redox homeostasis maintenance, epigenetic modification and signaling pathway regulation, particularly during embryonic development. Animal and human studies have increasingly documented that methionine deficiency or excess can negatively impact metabolic processes, translation, epigenetics, and signaling pathways, with ultimate detrimental effects on pregnancy outcomes. However, the underlying mechanisms by which methionine precisely regulates epigenetic modifications and affects signaling pathways remain to be elucidated. In this review, we discuss methionine and the metabolism of its metabolites, the influence of folate-mediated carbon metabolism, redox reactions, DNA and RNA methylation, and histone modifications, as well as the mammalian rapamycin complex and silent information regulator 1-MYC signaling pathway. This review also summarizes our present understanding of the contribution of methionine to these processes, and current nutritional and pharmaceutical strategies for the prevention and treatment of developmental defects in embryos.

Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies.

Specialized T cell subsets mediate adaptive immunity in response to cytokine signaling and specific transcription factor activity. The epigenetic landscape of T cells has an important role in facilitating and establishing T cell fate decisions. Here, we review the interplay between transcription factors, histone modifications, DNA methylation and three-dimensional chromatin organization to define key elements of the epigenetic landscape in T cells. We introduce key technologies in the areas of sequencing, microscopy and proteomics that have enabled the multi-scale profiling of the epigenetic landscape. We highlight the dramatic changes of the epigenetic landscape as multipotent progenitor cells commit to the T cell lineage during development and discuss the epigenetic changes that favor the emergence of CD4+ and CD8+ T cells. Finally, we discuss the inheritance of epigenetic marks and its potential effects on immune responses as well as therapeutic strategies with potential for epigenetic regulation.

Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.

With the growing scale of largemouth bass breeding, the demand for seedlings is increasing. As global temperatures rise, it is crucial to study the effects of high temperature their regulatory mechanisms in largemouth bass. In this study, we simulated a high water temperature (28 °C) in the non-breeding season in aquaculture ponds for 28 days to examine the growth, reproduction, metabolism, apoptosis, and methylation markers in largemouth bass; transcriptome analysis was also performed. The results showed no significant difference in body weight between male and female largemouth bass. However, the high-temperature exposed females had reduced growth hormone (GH) and estradiol (E2) levels and elevated cortisol levels. They also showed upregulated expression of AR, cyp19a, igf, fshβ, and lhβ in ovarian tissue. Transcriptomic comparisons between temperature treatments revealed 963 differentially expressed genes in females and 700 in males. Both the ECM receptor interaction and PPAR signaling pathways were significantly enriched. High-temperature enhanced the lipid metabolism process through the PPAR signaling pathway. High temperatures increased oxidative stress in females, which corresponded with increases in SOD, CAT, and GSH-Px, likely to counteract the excess reactive oxygen species. Moreover, endoplasmic reticulum stress was activated, indicated by increases in IRE1 and ATF6, leading to the upregulation of apoptosis-related genes and ovarian cell apoptosis. At high temperature, 5-MC%, demethylase, and methyltransferase were not different in females, while 5-MC% and methyltransferase were higher and demethylase was lower in males. In summary, sustained high temperature affected ovarian development by altering the expression of hormone and gonad related genes and inducing endoplasmic reticulum stress leading to ovarian cell apoptosis. However, low demethylase activity and high genome-wide methylation in the test is suggested that high temperatures may affect testis development via methylation, potentially impacting offspring production.

Drug abuse can damage the central nervous system and lead to substance use disorder (SUD). SUD is influenced by both genetic and environmental factors. Genes determine an individual's susceptibility to drug, while the dysregulation of epigenome drives the abnormal transcription processes, promoting the development of SUD. One of the most widely studied epigenetic mechanisms is DNA methylation, which can be inherited stably. In ontogeny, DNA methylation pattern is dynamic. DNA dysmethylation is prevalent in drug-related psychiatric disorders, resulting in local hypermethylation and transcriptional silencing of related genes. In this review, we summarize the role and regulatory mechanisms of DNA methylation in cocaine, opioids, and methamphetamine in terms of drug exposure, addiction memory, withdrawal relapse, intergenerational inheritance, and focus on cell-specific aspects of the studies with a view to suggesting possible therapeutic regimens for targeting methylation in both human and animal research.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The current diagnostic and therapeutic approaches need to be improved. Cellular senescence has been implicated in the pathogenesis of DN, but its precise role remains unclear. This study aimed to identify key pathogenic genes related to cellular senescence in DN and explore their potential as diagnostic biomarkers. Using transcriptomic data from GEO datasets (GSE96804, GSE30122, GSE142025, and GSE104948) and cellular senescence-related genes sourced from the GenAge database, we integrated multiple bioinformatics approaches, including differential expression analysis, weighted gene co-expression network analysis (WGCNA), machine learning and protein-protein interaction (PPI), to identify diagnostic genes. PTEN was identified as a key diagnostic gene. Immune infiltration analysis revealed that PTEN expression is positively correlated with macrophage M2 and dendritic cell resting infiltration and negatively correlated with monocytes and neutrophils. snRNA analysis revealed that PTEN is mainly expressed in mesangial cells. Finally, RT-PCR results revealed that the mRNA expression of PTEN was upregulated in kidneys from db/db mice. Additionally, high-glucose treatment significantly upregulated PTEN expression in cultured human mesangial cells. This study identifies PTEN as a potential diagnostic biomarker for DN which may contribute to early detection and personalized therapeutic strategies.

The bulk of RNA produced from the genome of complex organisms consists of a very large number of transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products of spurious transcriptional noise, ncRNAs are now universally recognized as pivotal players in cell regulatory networks across a broad spectrum of biological processes. Owing to their critical regulatory roles, ncRNA dysfunction is closely associated with the etiopathogenesis of various human malignancies, including cancer. As such, ncRNAs represent valuable diagnostic biomarkers as well as potential targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), the two most extensively studied classes in the field of ncRNA biology. After outlining key concepts of miRNA and lncRNA biogenesis pathways, we examine their multiple roles in mediating epigenetic regulation of gene expression and chromatin organization. Finally, by providing numerous examples of specific miRNAs and lncRNAs, we discuss how dysregulation of these mechanisms contributes to the onset and/or progression of various human diseases.

The identification of DNA methylation at specific sites is crucial for the early detection of cancer since DNA methylation is intimately associated to the occurrence and development of cancer. Herein, two types of sensors that can detect site-specific DNA methylation were developed to meet practical requirements using methylation sensitive restriction endonuclease and CRISPR/Cas12a. To accomplish rapid detection of target, an AciI-mediated CRISPR/Cas12a assay was developed by coupling AciI to recognize DNA methylation with Cas12a to identify site-specific DNA. Since protospacer adjacent motif (PAM)-dependent endonuclease activity and trans-cleavage activity of Cas12a, it is possible to detect site-specific DNA methylation within 2 h with high specificity and acceptable sensitivity. To satisfy the needs of trace target detection, we developed an GlaI-strand displacement amplification (SDA) assisted CRISPR/Cas12a system. The system converts double-stranded methylated DNA to abundant single-stranded by GlaI and SDA. Then, the combination of SDA and CRISPR/Cas12a enable cascades amplification of signal. The approach can therefore be used to detect methylation at different specified sites, even those without PAM, and can increase sensitivity with a detection limit down to 8.19 fM. Importantly, the assay can distinguish between colorectal cancer and precancerous tissue, as well as identify colorectal patients and healthy people. This study provides a new avenue for the development of new biosensors for methylation analysis, and the two methods devised have the potential to meet the multiple requirements of site-specific methylation testing in various clinical settings.

Developmental plasticity refers to an organism's ability to adjust its development in response to changing environmental conditions, leading to changes in behaviour, physiology, or morphology. This adaptability is crucial for survival and helps organisms to cope with environmental challenges throughout their lives. Understanding the mechanisms underlying developmental plasticity, particularly how environmental and ontogenetic factors shape functional traits, is fundamental for both evolutionary biology and conservation efforts. In this study we investigated the effects of early-life environmental conditions on the development of claw asymmetry in juvenile European lobsters (Homarus gammarus, N=244), a functional trait essential for survival and ecological success. Juveniles were randomly divided between four different rearing conditions characterized by the presence or absence of physical enrichments (e.g. substrate and shelters), which were introduced at different developmental stages in separated groups to assess the timing and nature of their effect. Results revealed that exposure to substrate alone, without additional stimuli, consistently promoted claw asymmetry, regardless of the timing of its introduction, while the 6th developmental stage emerged as the critical period for claw differentiation. By identifying the environmental factors that influence developmental outcomes in lobsters, and the timing of these effects, this study improves our understanding of developmental plasticity and offers valuable insights for optimizing conservation aquaculture and reintroduction strategies.

Stress can have powerful and lasting effects on our bodies and behavior, partly because it changes how our genes work. These processes, such as DNA methylation, histones modifications, and non-coding RNAs, help decide when genes are active or inactive in cells experiencing stress. This can lead to lasting changes in how the cells function. It's important to understand how these changes in our genes affect our response to stress, as they can lead to problems like anxiety, depression, and heart disease. This chapter explores the link between stress and epigenetics. It talks about how our surroundings and lifestyle can impact these processes. It also shows that epigenetic treatments might help with issues created by stress. By looking at how stress affects our genes, we can discover new ways to treat stress and make medicine better for individuals, helping to lessen the bad impact of stress on our health.

In post-genome-wide association study era, interpretation of noncoding variants remains a significant challenge due to their complexity and the limited understanding of their functions. Here, we developed MIRACN, a novel residual convolutional neural network designed to predict cell line-specific functional regulatory variants. By utilizing a substantial dataset from massively parallel reporter assays (MPRAs) and employing a multitask learning strategy, MIRACN was trained across seven distinct cell lines, attaining superior performance compared to existing methods, especially in predicting cell type specificity. Comparative evaluations on an independent MPRA test dataset demonstrated that MIRACN not only outperformed in identifying regulatory variants but also provided valuable insights into their cellular context-specific regulatory mechanisms. MIRACN is capable of not only providing scores for functional variants but also pinpointing the specific cell line in which these variants display their function. This enhancement has improved the resolution of current research on the functionality of noncoding variants and has paved the way for more precise diagnostic and therapeutic strategies.

This study aimed to explore the potential mechanism of Xiexin Tang in improving type 2 diabetes mellitus from the perspective of intestinal barrier function. The results indicated that Xiexin Tang could notably promote the expression of GPRs while suppressing the expression of HDACs in colon epithelial cells, then significantly elevate the levels of TGF-β1 and IL-18 to regulate the differentiation of T cells and further maintain the intestinal immune homeostasis. Meanwhile, it could markedly inhibit the inflammatory signaling pathway to improve intestinal barrier function, relieving type 2 diabetes mellitus.

Tubulointerstitial fibrosis (TIF) is present with chronic kidney disease (CKD). Vinpocetine (Vinpo) is used for treating cerebrovascular deficits, exhibiting some kidney-beneficial effects; however, its role in TIF is uncertain. So, the aim of this study was to investigate its potential impact on adenine-induced fibrotic CKD and explore the underlying mechanistic aspects. Eighteen male Wistar rats were categorized into three groups (n = 6 each). Group I was kept as controls and given saline; group II received adenine (300 mg/kg, twice weekly, i.p.) for induction of the CKD model; and group III was administered Vinpo (20 mg/kg/d, orally) concurrently with adenine. All treatments were administered for 4 weeks. Vinpo revealed an improvement in renal function and an alleviation of inflammation triggered by adenine via diminishing serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels. Further, Vinpo repressed the epithelial-mesenchymal transition (EMT) with preserved E-cadherin mRNA expression and lowered gene and immune expression of fibronectin and vimentin, respectively, besides attenuating the elevated G2/M arrest-related molecules (renal Ki67 protein contents and p21 gene expression). Renal pathological alterations caused by adenine were attenuated upon Vinpo administration. Interestingly, Vinpo suppressed abnormal renal β-catenin immunoreactivity, Snail 1, and MMP-7 gene expression while simultaneously restored Klotho protein expression by downregulating DNA methyltransferase 1 enzyme (DNMT1) protein expression in the kidney. These data indicated that Vinpo effectively mitigated EMT and G2/M arrest-induced renal fibrosis in adenine-induced CKD rats by targeting DNMT1-associated Klotho suppression, subsequently inhibiting β-catenin and its fibrotic downstream genes.

Identifying effective predictors early in life is crucial to enable timely prevention and intervention to improve cardiometabolic health outcomes. Adiposity rebound (AR) is an important period in early life, with earlier AR increasing the risk of cardiometabolic abnormalities. However, the role and mechanism of genetic factors in this association are unclear. Therefore, this study reviews the potential genetic mechanisms influencing the age at AR, as well as the genetic mechanisms linking earlier AR with cardiometabolic abnormalities.

A comprehensive literature search was conducted in PubMed and China National Knowledge Infrastructure databases using a combination of medical subject headings terms and related keywords, including "adiposity rebound", "cardiometabolic", "obesity", "BMI trajectory", "diabetes mellitus", "dyslipidemias", "hypertension", "metabolic syndrome", "genetics", and "epigenetic". Citation tracking was performed as a supplementary search strategy. All potentially relevant articles were subsequently subjected to full-text evaluation for eligibility assessment.

Polymorphisms in the DMRT1, FTO, LEPR, and TFAP2B genes, along with obesity susceptibility, can influence the age at AR. Single-nucleotide polymorphisms associated with the age at AR are enriched in the insulin-like growth factor 1 (IGF-1) signaling pathway, which can be modulated by the LEPR and TFAP2B genes. Shared genetic mechanisms between cardiometabolic abnormalities and the age at AR are influenced by obesity-related genetic variants. These variants regulate the growth hormone (GH)/IGF-1 axis, advancing AR and leading to cardiometabolic abnormalities. Earlier AR alters adiponectin and leptin levels, further activating the GH/IGF-1 axis and creating a vicious cycle. Long-term breastfeeding can counteract the adverse effects of obesity-related genetic susceptibility on AR timing, thereby reducing the genetic risk of cardiometabolic abnormalities.

Our results support earlier AR as a marker for identifying cardiometabolic risk and screening high-risk populations at the genetic level.

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. A common feature of this pathology is the impaired decidualization of endometrial stromal cells, a critical process that prepares the uterus for embryo implantation. This decidualization defect has been mechanistically linked to progesterone resistance in endometriotic lesions. However, the presence and underlying mechanisms of decidualization defects in the eutopic endometrium of women with endometriosis remain controversial. The aim of the present study is to integrate and discuss molecular evidence from both in vivo and in vitro studies examining decidualization alterations in the eutopic endometrium of patients with endometriosis. Multiple studies have demonstrated impaired decidualization in the eutopic endometrium of women with endometriosis. These alterations have been reported on multiple genes, signaling pathways, and epigenetic processes. However, additional functional studies are warranted to elucidate whether these decidualization defects directly contribute to endometriosis-associated infertility. A better understanding of the decidualization process and its dysregulation in endometriosis will not only advance the development of targeted fertility treatments but also facilitate the design of more effective therapeutic strategies for managing this chronic condition.

The early postnatal period is a critical neurodevelopmental stage characterized by rapid neural maturation and is adversely affected by early-life stressors. This study explored the behavioural, physiological, and epigenetic consequences of early-life stress in a population of homeless rescue kittens. This longitudinal study included 50 kittens rescued and placed into foster care by the Prince Edward Island Humane Society. They underwent behavioural testing at 8, 10, and 12 weeks of age. Hair cortisol concentration was measured at 8 weeks and served as a physiological marker of the previous 3 months' cumulative stress response, which, for these kittens, included the late gestation period. A blood sample for relative telomere length measurement was taken at 10-12 weeks to estimate epigenetic changes as young kittens. Data were analyzed with respect to age and performance in all repeated measures tests, status as a stray or a surrender, and the presence of the dam in their foster homes. As expected, the performance of kittens in all tests changed over the 5 weeks of testing. Kittens separated from their mothers exhibited significantly higher hair cortisol concentrations (p = 0.02) and elongated relative telomere lengths (p = 0.04). No correlation was found between hair cortisol concentration and relative telomere lengths (p = 0.99). These results support the need for further study on the effects of epigenetics and early-life stress, both in kittens and across species.

Cancer stands as a leading cause of mortality and poses an escalating threat to global health. Epigenetic dysregulation is pivotal in the onset and advancement of cancer. Recent research on RNA 5-methylcytosine (m5C) methylation has underscored its significant role in cancer. RNA m5C methylation is a key component in gene expression regulation and is intricately linked to cancer development, offering valuable insights for cancer diagnosis, treatment, and prognosis. This review provides an in-depth examination of the three types of regulators associated with RNA m5C methylation and their biological functions. It further investigates the expression and impact of RNA m5C methylation and its regulators in cancer, focusing on their mechanisms in cancer progression and clinical relevance. The current research on inhibitors targeting RNA m5C methylation-related regulators remains underdeveloped, necessitating further exploration and discovery.

This study presents a comprehensive analysis of recent mental illness research by utilizing an advanced bibliographic method capable of analyzing up to 12,965 papers indexed in the Web of Science database, overcoming the limitations of traditional tools like VOSviewer, which typically analyze fewer than 1,000 papers. By examining a vast dataset, this study identifies key trends, significant keywords, and prominent contributors, including leading researchers, universities, and countries/regions, in the field of mental illness research. Additionally, the study highlights eight major contributors to mental health problems, offering critical insights into the field’s current state. The findings underscore the importance of advanced bibliographic methods in providing a more detailed and accurate overview of mental illness research. This analysis not only enhances the understanding of young scholars entering the field but also uncovers significant trends and identifies notable gaps in the literature. The study advocates for continued innovation and interdisciplinary collaboration to deepen understanding and address unresolved challenges in mental health research.

Epigenetic regulation in hematopoietic stem cells (HSCs) research has emerged as a transformative molecular approach that enhances understanding of hematopoiesis and hematological disorders. This chapter investigates the intricate epigenetic mechanisms that control HSCs function, including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. It also explores the role of non-coding ribonucleic acid (RNAs) as epigenetic regulators, highlighting how changes in gene expression can occur without alterations to the DNA sequence. Epigenetic mechanisms play a pivotal in regulating HSC self-renewal and differentiation, processes essential for maintaining a balanced hematopoietic system in which lineage-specific hematopoietic stem and progenitor cells (HSPCs) pool is sustained. Recent advancements in epigenetic mapping and sequencing technologies have illuminated the dynamic epigenetic landscapes that characterize HSCs and their progeny. Numerous studies have revealed that dysregulation of epigenetic pathways is a hallmark of various hematological malignancies, including leukemias, lymphomas, and myelodysplastic syndromes. This review highlights key findings that demonstrate the impact of epigenetic abnormalities on the disruption of HSPC niches and the progression of oncogenesis in hematological malignancies. Furthermore, this chapter explores the therapeutic potential of targeting epigenetic modifications that are critical in formation and progression of hematologic malignancies. It also discusses the latest developments in epigenetic therapies, including the use of DNA methyltransferase inhibitors, histone deacetylase inhibitors, and emerging drugs targeting other epigenetic regulators. These therapies represent a promising strategy for resetting aberrant epigenetic states, potentially restoring normal hematopoiesis. Conclusively, this chapter offers a thorough overview of the current landscape and future directions of epigenetic research related to the maintenance of the HSPC niches. The insights presented here aim to contribute significantly to the field, offering a reference point for molecular approaches that enhance our understanding of hematopoiesis and its associated hematological malignancies.

Adolescence is a conserved neurodevelopmental period encompassing maturation of glia and the innate immune system that parallels refinement of brain structures, neurotransmitter systems, and neurocircuitry. Given the vast neurodevelopmental processes occurring during adolescence, spanning brain structural and neurocircuitry refinement to maturation of neurotransmitter systems, glia, and the innate immune system, insults incurred during this critical period of neurodevelopment, could have profound effects on brain function and behavior that persist into adulthood. Adolescent binge drinking is common and associated with many adverse outcomes that may underlie the lifelong increased risk of alcohol-related problems and development of an alcohol use disorder (AUD). In this chapter, we examined the impact of adolescent binge drinking models using the adolescent intermittent ethanol (AIE) model on adult neurobiology. These studies implicate proinflammatory neuroimmune signaling across glia and neurons in persistent AIE-induced neuropathology. Some of these changes are reversible, providing unique opportunities for the development of treatments to prevent many of the long-term consequences of adolescent alcohol misuse.

Three-dimensional (3D) chromatin interactions, such as enhancer-promoter interactions (EPIs), loops, topologically associating domains (TADs), and A/B compartments, play critical roles in a wide range of cellular processes by regulating gene expression. Recent development of chromatin conformation capture technologies has enabled genome-wide profiling of various 3D structures, even with single cells. However, current catalogs of 3D structures remain incomplete and unreliable due to differences in technology, tools, and low data resolution. Machine learning methods have emerged as an alternative to obtain missing 3D interactions and/or improve resolution. Such methods frequently use genome annotation data (ChIP-seq, DNAse-seq, etc.), DNA sequencing information (k-mers and transcription factor binding site (TFBS) motifs), and other genomic properties to learn the associations between genomic features and chromatin interactions. In this review, we discuss computational tools for predicting three types of 3D interactions (EPIs, chromatin interactions, and TAD boundaries) and analyze their pros and cons. We also point out obstacles to the computational prediction of 3D interactions and suggest future research directions.

Epigenetic modifications have been identified as critical molecular determinants influencing macrophage plasticity and heterogeneity. Among these, histone lactylation is a recently discovered epigenetic modification. Research examining the effects of histone lactylation on macrophage activation and polarization has grown substantially in recent years. Evidence increasingly suggests that lactate-mediated changes in histone lactylation levels within macrophages can modulate gene transcription, thereby contributing to the pathogenesis of various diseases. This review provides a comprehensive analysis of the role of histone lactylation in macrophage activation, exploring its discovery, effects, and association with macrophage diversity and phenotypic variability. Moreover, it highlights the impact of alterations in macrophage histone lactylation in diverse pathological contexts, such as inflammation, tumorigenesis, neurological disorders, and other complex conditions, and demonstrates the therapeutic potential of drugs targeting these epigenetic modifications. This mechanistic understanding provides insights into the underlying disease mechanisms and opens new avenues for therapeutic intervention.

Diabetes is a major risk factor for compromised visual health, leading to retinal vasculopathy and neuropathy, both of which are hallmarks of neurovascular unit dysfunction. Despite the critical impact of diabetic retinopathy, the precise mechanism underlying neurovascular coupling and effective strategies to suppress neurovascular dysfunction remain unclear. In this study, the up-regulation of a tRNA-derived stress-induced RNA, 5'tiRNA-His-GTG, in response to diabetic stress is revealed. 5'tiRNA-His-GTG directly regulates Müller glia action and indirectly alters endothelial angiogenic effects and retinal ganglion cell (RGC) survival in vitro. Downregulation of 5'tiRNA-His-GTG alleviates diabetes-induced retinal neurovascular dysfunction, characterized by reduced retinal vascular dysfunction, decreased retinal neurodegeneration, and improved visually-guided behaviors in vivo. Mechanistically, 5'tiRNA-His-GTG acts as a key regulator of retinal neurovascular dysfunction, primarily by modulating arachidonic acid (AA) metabolism via the CYPs pathway. The 5'tiRNA-His-GTG-CYP2E1-19(S)-HETE signaling axis is identified as a key driver of retinal neurovascular dysfunction. Thus, targeting 5'tiRNA-His-GTG presents a promising therapeutic strategy for treating vasculopathy and neuropathy associated with diabetes mellitus. Modulating this novel signaling pathway can open up new avenues for intervention in diabetic retinopathy and its related complications.

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

This review aims to explore the pivotal role of long non-coding RNAs (lncRNAs) as epigenetic regulators in the pathogenesis of multiple myeloma (MM). Additionally, we have portrayed the dual role of lncRNAs in the epigenetic landscape of MM pathobiology.

In MM, lncRNAs are pivotal for proliferation, progression, and drug resistance by acting as miRNA sponges, regulating mRNA activity through microRNA recognition elements (MREs). Epigenetic modifications in lncRNAs influence gene expression, with some like MEG3, GAS5, CRNDE, and H19 showing promoter hypermethylation, while MALAT1 exhibits hypomethylation. Targeting lncRNAs using siRNA, ASO, CRISPR-Cas9, or small molecule inhibitors shows promise in preclinical studies, alongside the potential benefits of epigenetic-based therapies such as DNMTi and HDACi. Clinical trials combining epigenetic modifiers with standard chemotherapy show encouraging results, especially in relapsed/refractory MM. The key finding of the studies highlighted in the review paves the way for understanding the epigenetic role of lncRNAs in MM disease progression and biology. In addition, the novel therapeutic strategies that have shown promising results have been highlighted. The adoption of the epigenetic landscape into therapeutics in addition to existing treatment strategies may increase the efficacy of treatment approaches.

Epigenetic factors are crucial for ensuring proper chromatin dynamics during the initial stages of embryo development. Among these factors, the Polycomb group (PcG) of proteins plays a key role in establishing correct transcriptional programmes during mouse embryogenesis. PcG proteins are classified into two complexes: Polycomb repressive complex 1 (PRC1) and PRC2. Both complexes decorate histone proteins with distinct post-translational modifications (PTMs) that are predictive of a silent transcriptional chromatin state. In recent years, a critical adaptation of the classical techniques to analyse chromatin profiles and to study biochemical interactions at low-input resolution has allowed us to deeply explore PcG molecular mechanisms in the very early stages of mouse embryo development- from fertilisation to gastrulation, and from zygotic genome activation (ZGA) to specific lineages differentiation. These advancements provide a foundation for a deeper understanding of the fundamental role Polycomb complexes play in early development and have elucidated the mechanistic dynamics of PRC1 and PRC2. In this review, we discuss the functions and molecular mechanisms of both PRC1 and PRC2 during early mouse embryo development, integrating new studies with existing knowledge. Furthermore, we highlight the molecular functionality of Polycomb complexes from ZGA through gastrulation, with a particular focus on non-canonical imprinted and bivalent genes, and Hox cluster regulation.

Recent studies have shown that dysfunction in chromatin regulators (CRs) may be an important mechanism of myocardial infarction (MI). They are thus expected to become a new target in the diagnosis and treatment of MI. However, the diagnostic value of CRs in MI and the mechanisms are not clear.

CRs-related differentially expressed genes (DEGs) were screened between healthy controls and patients with MI via GSE48060, GSE60993, and GSE66360 datasets. DEGs were further analyzed for enrichment analysis. Hub genes were screened by least absolute shrinkage and selection operator (LASSO) regression and weighted gene co-expression network analysis (WGCNA). GSE61144 datasets were further used to validate hub genes. RT-qPCR examined peripheral blood mononuclear cells (PBMCs) to verify expressions of hub genes. In addition, a correlation between hub genes and immune cell infiltration was identified by CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Finally, we constructed a diagnostic nomogram and ceRNA network and found possible therapeutic medicines which were based on hub genes.

Firstly, 16 CR-related DEGs were identified. Next, Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and transcriptional regulator Jun dimerization protein 2 (JDP2) were selected as hub genes by LASSO and WGCNA. Receiver operating characteristic curves in the training and test data sets verified the reliability of hub genes. Results of RT-qPCR confirmed the upregulation of hub genes in MI. Subsequently, the immune infiltration analysis indicated that DUSP1, GADD45A, and JDP2 were correlated with plasmacytoid dendritic cells, natural killer cells, eosinophils, effector memory CD4 T cells, central memory CD4 T cells, activated dendritic cells, and activated CD8 T cells. Furthermore, a nomogram that included DUSP1, GADD45A, and JDP2 was created. The calibration curve, decision curve analysis, and the clinical impact curve indicated that the nomogram could predict the occurrence of MI with high efficacy. The results of the ceRNA network suggest that hub genes may be cross-regulated by various lncRNAs and miRNAs. In addition, 10 drugs, including 2H-1-benzopyran, Nifuroxazide, and Bepridil, were predicted to be potential therapeutic agents for MI.

Our study identifies three promising genes associated with the progression of chromatin regulators (CRs)-related myocardial infarction (MI) and immune cell infiltration, including Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and Jun dimerization protein 2 (JDP2), which might be worthy of further study.

Identifying differentially methylated cytosine-guanine dinucleotide (CpG) sites between benign and tumour samples can assist in understanding disease. However, differential analysis of bounded DNA methylation data often requires data transformation, reducing biological interpretability. To address this, a family of beta mixture models (BMMs) is proposed that (i) objectively infers methylation state thresholds and (ii) identifies differentially methylated CpG sites (DMCs) given untransformed, beta-valued methylation data. The BMMs achieve this through model-based clustering of CpG sites and by employing parameter constraints, facilitating application to different study settings. Inference proceeds via an expectation-maximisation algorithm, with an approximate maximization step providing tractability and computational feasibility. Performance of the BMMs is assessed through thorough simulation studies, and the BMMs are used for differential analyses of DNA methylation data from a prostate cancer study. Intuitive and biologically interpretable methylation state thresholds are inferred and DMCs are identified, including those related to genes such as GSTP1, RASSF1 and RARB, known for their role in prostate cancer development. Gene ontology analysis of the DMCs revealed significant enrichment in cancer-related pathways, demonstrating the utility of BMMs to reveal biologically relevant insights. An R package betaclust facilitates widespread use of BMMs.