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.

Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.

Cells preserve and convey certain gene expression patterns to their progeny through the mechanism called epigenetic memory. Epigenetic memory, encoded by epigenetic markers and components, determines germline inheritance, genomic imprinting, and X chromosome inactivation. First discovered long non coding RNAs were implicated in genomic imprinting and X-inactivation and these two phenomena clearly demonstrate the role of lncRNAs in epigenetic memory regulation. Undoubtedly, lncRNAs are well-suited for regulating genes in close proximity at imprinted loci. Due to prolonged association with the transcription site, lncRNAs are able to guide chromatin modifiers to certain locations, thereby enabling accurate temporal and spatial regulation. Nevertheless, the current state of knowledge regarding lncRNA biology and imprinting processes is still in its nascent phase. Herein, we provide a synopsis of recent scientific advancements to enhance our comprehension of lncRNAs and their functions in epigenetic memory, with a particular emphasis on genomic imprinting and X chromosome inactivation, thus gaining a deeper understanding of the role of lncRNAs in epigenetic regulatory networks.

Autoimmune polyendocrine syndrome Type-1 (APS-1) is a rare, but severe organ-specific autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Lack of AIRE causes autoreactive T cells to escape negative selection and alters the T regulatory cell subset. However, little is known about how the immune cell subsets vary across the lifespan in APS-1. Here we analysed the peripheral distribution of 13 immune cell subsets along the lifespan using epigenetic quantification. We found the largest discrepancy in immune cells to appear early in APS-1 patients' lives, coinciding with the time point they obtained most of their clinical symptoms. We further revealed longitudinal changes in cell compositions both within the adaptive and the innate arms of the immune system. We found that cell frequencies of B cells, T-cell subgroups, nonclassical monocytes, and Natural Killer cells to be reduced in young APS-1 patients. We also found B-cell frequencies to decrease with ageing in both patients and healthy controls. Our results suggest that Tregs, follicular helper T, and natural killer cells have opposing trends of cell frequencies during life, indicating the importance of considering the age profiles of cohorts which could otherwise lead to conflicting conclusions.

Microcystin-LR's reproductive (reproductive and non-reproductive periods) and transgenerational toxicity in amphibians remains poorly understood. Adult Pelophylax nigromaculatus in reproductive and non-reproductive periods were exposed to MC-LR to investigate whether there are differences in the effects of MC-LR on reproductive endocrinology between reproductive and non-reproductive periods of amphibians. Furthermore, cross-mating experiments between MC-LR-exposed and non-exposed frogs in reproductive periods were conducted to explore transgenerational effects. Compared to P. nigromaculatus without MC-LR exposure, exposure to MC-LR resulted in an increase in testosterone synthesis levels and a decrease in estradiol synthesis levels during the reproductive period, but a decrease in testosterone synthesis levels and an increase in estradiol synthesis levels during the non-reproductive period. High lipid contents in the gonads during the reproductive period substantially enriched MC-LR, increasing DNA damage and methylation levels. This may be the reason for the observed opposite trend in sex hormone synthesis levels compared to the non-reproductive period. Additionally, the hypothalamic-pituitary-gonadal-liver axis in F1 tadpoles was disrupted, leading to gonadal dysgenesis, particularly in the ovaries. The observed transgenerational reproductive toxicity may be attributed to decreased gamete quality, transgenerational transfer of MC-LR, and increased DNA methylation level. This study provides novel insights into the differential reproductive endocrine disruption effects of MC-LR during different periods and highlights its transgenerational reproductive toxicity for the first time, underscoring the need for further research on MC-LR's impact on amphibian population dynamics.

Diabetic retinopathy, a microvascular complication of diabetes, is the leading cause of blindness in adults, but the molecular mechanism of its development remains unclear. Retinal mitochondrial DNA is damaged and hypermethylated, and mtDNA-encoded genes are downregulated. Expression of a long noncoding RNA (larger than 200 nucleotides, which does not translate into proteins), encoded by mtDNA, cytochrome B (LncCytB), is also downregulated. This study aims to investigate the role of DNA methylation in the downregulation of LncCytB in diabetic retinopathy. Human retinal endothelial cells, incubated in 5 mM (normal) or 20 mM (high) D-glucose, in the presence/absence of Azacytidine (a DNA methyl transferase inhibitor) were analyzed for LncCytB DNA methylation by immunoprecipitation and methylation specific PCR techniques, and LncCytB transcripts by strand-specific PCR and RNA-FISH. Mitochondrial genomic stability was evaluated by quantifying protective mtDNA nucleoids by SYBR green staining and by flow cytometry, and functional stability by oxygen consumption rate using Seahorse analyzer. Results were confirmed in an in vivo model using retina from diabetic rat. While high glucose elevated 5 mC and the ratio of methylated to unmethylated amplicons at LncCytB and downregulated its transcripts, azacytidine prevented LncCytB DNA hypermethylation and decrease in its expression. Azacytidine also ameliorated decrease in nucleoids and oxygen consumption rate. Similarly, azacytidine prevented increase in retinal LncCytB DNA methylation and decrease in its expression in diabetic rats. Thus, DNA hypermethylation plays a major role in the downregulation of retinal LncCytB in diabetes, resulting in impaired mitochondrial homeostasis, and culminating in the development of diabetic retinopathy.

Over the years, the rearing period of the commercial broilers to attain the slaughter weight has reduced significantly. Hence, it emphasizes the importance of the period of embryonic development. It has been shown that inadequate nutritional supply to the embryo at the later phases can lead to various abnormalities. This adversely affects the hatchability and further the post-hatch performance of the chicks. This study attempted to study the effect of in ovo feeding of sericin on the developing Ross-308 embryos. Fertile eggs (n = 210) at 17.5 days of embryonic development (ED) were equally divided into five treatments based on the concentration of sericin fed. The treatments were: uninjected control (UCON), followed by different concentrations of sericin injected groups as 0SER (0 % sericin), 1.5SER (1.5 % sericin), 3.0SER (3.0 % sericin), and 4.5SER (4.5 % sericin). Hatch parameters across treatments did not differ significantly. Similarly, the organ (liver, yolk sac, gizzard, proventriculus and heart) indices and plasma antioxidant markers such as 2,2-Diphenyl-1-picrylhydrazyl - radical scavenging activity % (DPPH-RSA%) and malondialdehyde (MDA) content did not differ significantly across treatments. The hepatic mRNA expression of superoxide dismutase (SOD) was higher in 3.0SER treatment in comparison to 4.5SER. On the other hand, in ovo sericin downregulated the hepatic gene expression of DNA demethylation-related enzymes such as ten-eleven translocation methylcytosine dioxygenase 3 (TET3, p = 0.028) and methyl-CpG-binding domain protein 4 (MBD4, p = 0.007) compared to 0SER. Pearson's correlation analyses revealed a significant correlation between the hepatic gene expression of NADPH oxidase (NOX) related genes and DNA-demethylation-related genes (p < 0.01). Hence, in ovo sericin might not be potentially beneficial in improving the hatchability of broilers. Also, no notable effects on the antioxidant capacity of plasma was recorded. However, in ovo sericin downregulated the mRNA expression of some DNA demethylation-related genes which were significantly correlated with the expression of NOXs. Therefore, in ovo sericin feeding could suppress DNA demethylation which could in turn be beneficial to alleviate oxidative stress at hatch.

Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.

This study aimed to assess how ursolic acid (UA) can protect human skin keratinocytes from damage caused by UVB radiation. Utilizing an omics-based approach, we characterized the features of photodamage and investigated the potential of UA to reverse HaCaT cell subpopulation injury caused by UVB radiation. The most significant changes in metabolite levels after UA treatment were in pathways associated with phosphatidylcholine biosynthesis and arginine and proline metabolism. Treatment with UA can reverse the levels of certain metabolites, including creatinine, creatine phosphate, and succinic acid. Pathways activated by UA treatment in UVB-irradiated HaCaT cells were associated with several biological processes, including the positive regulation of protein modification process, cell division, and enzyme-linked receptor protein signaling pathway. Treatment with UA demonstrates the capability to mitigate the effects of UVB radiation on specific genes, including S100 calcium-binding protein A9 and IL6 receptor. DNA/CpG methylation indicates that UA can partially reverse some of the alterations in the UVB-induced CpG methylome. Utilizing integrated RNA sequencing and methylation sequencing data, starburst plots illustrate the correlation between mRNA expression and CpG methylation status. UA potentially influences the metabolic pathway of glycerophospholipid metabolism by modulating the expression of several key enzymes, including phospholipase A2 group IIA and lipin 2. Altogether, these results indicate that UVB radiation induces metabolic reprogramming, epigenetic changes, and transcriptomic shifts. Meanwhile, UA demonstrates the capacity to inhibit or reduce the severity of these alterations, which may underlie its potential protective role against skin damage caused by UVB exposure. Prevention Relevance: Our research indicates that UA has the potential to mitigate or lessen the impact of UVB radiation, which is known to cause metabolic reprogramming, epigenetic alterations, and transcriptomic changes. These effects could be responsible for UA's possible protective function against skin damage induced by UVB exposure.

Alzheimer's disease (AD) is characterized by amyloid pathology and neuroinflammation, leading to cognitive decline. Targeting histone deacetylase-11 (HDAC11) offers a novel therapeutic strategy due to its role in immune regulation.

We conducted neuropathological analyses on human AD post mortem brain tissues and 5xFAD transgenic mice. We developed PB94, a brain-permeable HDAC11-selective inhibitor, and assessed its effects using live-animal imaging and behavioral studies.

HDAC11 was significantly upregulated in AD brains, correlating with amyloid pathology and neuroinflammatory markers. PB94 treatment reduced amyloid burden and neuroinflammation, improving cognitive function in 5xFAD mice.

Our findings highlight HDAC11 as a promising drug target for AD. PB94's ability to reduce amyloid pathology and neuroinflammation suggests its potential as an effective therapeutic. This study supports further exploration of HDAC11 inhibition as a treatment strategy for AD.

Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease (AD) brains and colocalizes with amyloid pathology and neuroinflammatory markers. Novel brain-permeable HDAC11-selective inhibitor PB94 demonstrates promising therapeutic potential for AD treatment. PB94 treatment reduces amyloid burden and neuroinflammation in AD mouse models, confirmed by live imaging studies. HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels. PB94 treatment improves cognitive function in AD mouse models while showing favorable brain penetration and selectivity.

Chronic kidney disease (CKD) is a highly prevalent global public health issue and can progress to kidney failure. Survivors of acute kidney injury (AKI) have an increased risk of progressing to CKD by 8.8-fold and kidney failure by 3.1-fold. Further, 20% to 40% of individuals with diabetes will develop CKD, also known as diabetic kidney disease (DKD). Thus, preventing these kidney diseases can positively impact quality-of-life and life-expectancy outcomes for affected individuals. Frequent episodes of hyperglycemia and renal hypoxia are implicated in the pathophysiology of CKD. Prior periods of hyperglycemia/uncontrolled diabetes can result in development/progression of DKD even after achieving normoglycemia, a phenomenon known as metabolic memory or legacy effect. Similarly, in AKI, hypoxic memory is stored in renal cells even after recovery from the initial AKI episode and can transition to CKD. Epigenetic mechanisms involving DNA methylation, chromatin histone post-translational modifications, and noncoding RNAs are implicated in both metabolic and hypoxic memory, collectively known as "epigenetic memory." This epigenetic memory is generally reversible and provides a therapeutic avenue to ameliorate persistent disease progression due to hyperglycemia and hypoxia and prevent/ameliorate CKD progression. Indeed, therapeutic strategies targeting epigenetic memory are effective at preventing CKD development/progression in experimental models of AKI and DKD. Here, we review the latest in-depth evidence for epigenetic features in DKD and AKI, and in epigenetic memories of AKI-to-CKD transition or DKD development and progression, followed by translational and clinical implications of these epigenetic changes for the treatment of these widespread kidney disorders.

One of the most frequent forms of maternal morbidity following childbirth is postpartum depression. Postpartum depression (PPD), a disabling condition as a major public health concern, has a significant negative impact on the child's emotional, mental as well as intellectual development if left undiagnosed and untreated, which can later have long-term complications. The oxytocin system is an excellent candidate gene system in the maternal context. Differences in vulnerability of mothers for the onset of postpartum psychiatric disorders could be influenced by individual differences in the genetic profile of each one. In this original research, we aimed to explore if there are any possible contributions of genetic variation on both the oxytocin receptor gene (OXTR) and the oxytocin gene (OXT) to the occurrence of postpartum depression, aiming to provide the latest evidence and determine which genetic polymorphisms significantly create a susceptibility for this condition. A total of 100 mothers were preliminarily genotyped before they completed the Edinburgh Postnatal Depression Scale Questionnaire (EPDS) at 6 weeks postpartum. DNA was extracted from peripheral blood samples of the participants (N = 100) and evaluated for the oxytocin gene (OXT_rs2740210; OXT_rs4813627) and oxytocin receptor gene (OXTR_ rs237885) single nucleotide polymorphisms. The results highlighted a significant interaction between the oxytocin OXT_rs2740210 genotype and maternal postpartum depression in mothers with the CC genotype but not in those with AA/AC genotypes. This reveals that an interaction of vulnerable genotypes (CC genotype of OXT_rs2740210, C allele in genotype of OXT_rs2740210, G allele in genotype of OXT_rs4813627) with an environmental burden or other risk factors would predispose the mothers to develop postpartum depression. We found no significant association between the interaction effect of the oxytocin receptor gene OXTR_rs237885 genotype depending on the occurrence of maternal postpartum depression. These findings prove the implication of the oxytocinergic system gene variants in vulnerability for postpartum depression and indicate the need for future studies adopting a multilevel approach in order to increase understanding.

This study tests the association of whole-blood DNA methylation and antidepressant exposure in 16,531 individuals from Generation Scotland (GS), using self-report and prescription-derived measures. We identify 8 associations and a high concordance of results between self-report and prescription-derived measures. Sex-stratified analyses observe nominally significant increased effect estimates in females for four CpGs. There is observed enrichment for genes expressed in the Amygdala and annotated to synaptic vesicle membrane ontology. Two CpGs (cg15071067; DGUOK-AS1 and cg26277237; KANK1) show correlation between DNA methylation with the time in treatment. There is a significant overlap in the top 1% of CpGs with another independent methylome-wide association study of antidepressant exposure. Finally, a methylation profile score trained on this sample shows a significant association with antidepressant exposure in a meta-analysis of eight independent external datasets. In this large investigation of antidepressant exposure and DNA methylation, we demonstrate robust associations which warrant further investigation to inform on the design of more effective and tolerated treatments for depression.

Parental substance abuse increases the risk of neurological and psychiatric disorders in offsprings. However, its underlying mechanism remains elusive. Our previous study demonstrated that long-term exposure to methamphetamine (Meth), a psychostimulant drug with high addiction potential, remarkably alters the gut microbiome and metabolites in male mice, which contribute to Meth-induced anxiety-like behaviors. The current study aimed to investigate whether gut microbiota and metabolism serve as potential peripheral targets for transgenerational mental problems by paternal Meth exposure. We found that paternal Meth exposure induced depression-like behaviors both in the first (F1) and the second (F2) generations of male mice. Further, the depletion of gut bacteria through antibiotic treatments normalized the depression-like behaviors to normal levels in both F1 and F2 male mice. Then, alterations in gut bacterial composition were observed in both F1 and F2 male mice. Specifically, Eubacterium_ruminantium_group, Enterorhabdus, Alloprevotella, and Parabacteroides were the commonly affected bacterial taxa in F1 and F2 male mice. In addition, the results of alterations in gut metabolism showed that LPC 14:1-SN1 emerged as the consistently altered metabolite in the colons of F1 and F2 male mice. Taken together, our findings provide the first evidence that paternal Meth exposure enhances depression-like behaviors in F1 and F2 male mice, potentially mediated by the gut microbiome and metabolism.

Vascular smooth muscle cells (VSMCs) in adult arteries maintain substantial phenotypic plasticity, which allows for the reversible cell state changes that enable vascular remodelling and homeostasis. In atherosclerosis, VSMCs dedifferentiate in response to lipid accumulation and inflammation, resulting in loss of their characteristic contractile state. Recent studies showed that individual, pre-existing VSMCs expand clonally and can acquire many different phenotypes in atherosclerotic lesions. The changes in gene expression underlying this phenotypic diversity are mediated by epigenetic modifications which affect transcription factor access and thereby gene expression dynamics. Additionally, epigenetic mechanisms can maintain cellular memory, potentially facilitating reversion to the contractile state. While technological advances have provided some insight, a comprehensive understanding of how VSMC phenotypes are governed in disease remains elusive. Here we review current literature in light of novel insight from studies at single-cell resolution. We also discuss how lessons from epigenetic studies of cellular regulation in other fields could help in translating the potential of targeting VSMC phenotype conversion into novel therapies in cardiovascular disease.

Altered tissue mechanics is a prominent feature of many pathological conditions including cancer. As such, much work has been dedicated to understanding how mechanical features of tissues contribute to pathogenesis. Interestingly, previous work has demonstrated that the tumor vasculature acquires pathological features in part due to enhanced tumor stiffening. To further understand how matrix mechanics may be translated into altered cell behavior and ultimately affect tumor vasculature function, we have investigated the effects of substrate stiffening on endothelial epigenetics. Specifically, we have focused on DNA methylation as recent work indicates DNA methylation in endothelial cells can contribute to aberrant behavior in a range of pathological conditions.

Human umbilical vein endothelial cells (HUVECs) were seeded on stiff and compliant collagen-coated polyacrylamide gels and allowed to form monolayers over 5 days. DNA methylation was assessed via 5-methylcytosine ELISA assays and immunofluorescent staining. Gene expression was assessed via qPCR on RNA isolated from HUVECs seeded on collagen-coated polyacrylamide gels of varying stiffness.

Our work demonstrates that endothelial cells cultured on stiffer substrates exhibit lower levels of global DNA methylation relative to endothelial cells cultured on more compliant substrates. Interestingly, gene expression and DNA methylation dynamics suggest stiffness-mediated gene expression may play a role in establishing or maintaining differential DNA methylation levels in addition to enzyme activity. Additionally, we found that the process of passaging induced higher levels of global DNA methylation.

Altogether, our results underscore the importance of considering cell culture substrate mechanics to preserve the epigenetic integrity of primary cells and obtain analyses that recapitulate the primary environment. Furthermore, these results serve as an important launching point for further work studying the intersection tissue mechanics and epigenetics under pathological conditions.

Traditional Chinese Medicine (TCM), an ancient health system, faces significant research challenges due to the complexity of its active components and targets, as well as a historical lack of detailed annotation. However, recent advances in omics technologies have begun to unravel these complexities, providing a more informed and nuanced understanding of TCM's therapeutic potential in contemporary healthcare.

This review summarizes the application of omics technologies in TCM modernization, emphasizing components analysis, quality control, biomarker discovery, target identification, and treatment optimization. In addition, future perspectives on using omics for precision TCM treatment are also discussed.

We have explored several databases (including PubMed, ClinicalTrials, Google Scholar, and Web of Science) to review related articles, focusing on Traditional Chinese Medicine, Omics Strategy, Precision Medicine, Biomarkers, Quality Control, and Molecular Mechanisms. Paper selection criteria involved English grammar, publication date, high citations, and broad applicability, exclusion criteria included low credibility, non-English publications, and those full-text inaccessible ones.

TCM and the popularity of Chinese herbal medicines (CHMs) are gaining increasing attention worldwide. This is driven, in part, by a large number of technologies, especially omics strategy, which are aiding the modernization of TCM. They contribute to the quality control of CHMs, the identification of cellular targets, discovery of new drugs and, most importantly, the understanding of their mechanisms of action.

To fully integrate TCM into modern medicine, further development of robust omics strategies is essential. This vision includes personalized medicine, backed by advanced computational power and secure data infrastructure, to facilitate global acceptance and seamless integration of TCM practices.

Zygotic genome activation (ZGA) initiates transcription in early embryogenesis and requires extensive chromatin remodeling, including rapid incorporation of the histone variant H3.3. The distinct sources of H3.3 from paternal and maternal alleles (paH3.3 and maH3.3) complicate tracking their individual contributions. Here, using an H3.3B-hemagglutinin (HA)-tagged mouse model, we profile the temporal dynamics of paH3.3 and maH3.3, revealing a unique pattern of maH3.3 enrichment at the promoter regions from zygotes to 2-cell embryos, highlighting the crucial role of maternally stored H3.3 mRNAs and proteins (mH3.3) in pre-implantation development. Knockdown of mH3.3 compromises cleavage and minor ZGA. Mechanistically, mH3.3 facilitates minor ZGA through H3.3S31ph-dependent H3K27ac deposition. Profiling of H3.3 landscape in parthenogenetic (PG) and androgenetic (AG) embryos highlights the role of mH3.3 in remodeling the paternal genome by establishing H3K27ac. These findings demonstrate that mH3.3-mediated parental chromatin reprogramming is essential for orchestrating minor ZGA.

The burgeoning field of environmental epigenetics has revealed the malleability of the epigenome and uncovered numerous instances of its sensitivity to environmental influences; however, pinpointing specific mechanisms that tie together environmental triggers, epigenetic pathways, and organismal responses has proven difficult. This article describes how Caenorhabditis elegans can fill this gap, serving as a useful model for the discovery of molecular epigenetic mechanisms that are conserved in humans.

Recent results show that environmental stressors such as methylmercury, arsenite, starvation, heat, bacterial infection, and mitochondrial inhibitors can all have profound effects on the epigenome, with some insults showing epigenetic and organismal effects for multiple generations. In some cases, the pathways connecting the stressor to epigenetic pathways and organismal responses have been elucidated. For example, a small RNA from the bacterial pathogen Pseudomonas aeruginosa induces transgenerational learned avoidance by activating the RNA interference PIWI-interacting RNA pathways across generations to downregulate, via Cer1 retrotransposon particles and histone methylation, maco-1, a gene that functions in sensory neurons to regulate chemotaxis. Mitochondrial inhibitors seem to have a profound effect on both the DNA methylation mark 6mA and histone methylation, and may act within mitochondrial DNA (mtDNA) to regulate mitochondrial stress response genes. Transgenerational transcriptional responses to alcohol have also been worked out at the single-nucleus resolution in C. elegans, demonstrating its utility when combined with modern sequencing technologies. These recent studies highlight how C. elegans can serve as a bridge between biochemical in vitro experiments and the more associative findings of epidemiological studies in humans to unveil possible mechanisms of environmental influence on the epigenome. The nematode is particularly well-suited to transgenerational experiments thanks to its rapid generation time and ability to self-fertilize. These studies have revealed connections between the various epigenetic mechanisms, and so studies in C. elegans that take advantage of recent advancements in sequencing technologies, including single-cell techniques, to gain unprecedented resolution of the whole epigenome across development and generations will be critical.

The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.

Epigenetic dysregulation is an important nexus in the development and maintenance of human cancers. This review provides an overview of how understanding epigenetic dysregulation in cancers has led to insights for novel cancer therapy development. Over the past two decades, significant strides have been made in drug discovery efforts targeting cancer epigenetic mechanisms, leading to successes in clinical development and approval of cancer epigenetic therapeutics. This article will discuss the current therapeutic rationale guiding the discovery and development of epigenetic therapeutics, key learnings from clinical experiences and new opportunities on the horizon.

Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio-engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer-drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing.

The complex mechanisms underlying the development of cardiovascular diseases remain not fully elucidated. Epigenetics, which modulates gene expression without DNA sequence changes, is shedding light on these mechanisms and their heritable effects. This review focus on epigenetic regulation in cardiovascular aging and diseases, detailing specific epigenetic enzymes such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), which serve as writers or erasers that modify the epigenetic landscape. We also discuss the readers of these modifications, such as the 5-methylcytosine binding domain proteins, and the erasers ten-eleven translocation (TET) proteins. The emerging role of RNA methylation, particularly N6-methyladenosine (m6A), in cardiovascular pathogenesis is also discussed. We summarize potential therapeutic targets, such as key enzymes and their inhibitors, including DNMT inhibitors like 5-azacytidine and decitabine, HDAC inhibitors like belinostat and givinotide, some of which have been approved by the FDA for various malignancies, suggesting their potential in treating cardiovascular diseases. Furthermore, we highlight the role of novel histone modifications and their associated enzymes, which are emerging as potential therapeutic targets in cardiovascular diseases. Thus, by incorporating the recent studies involving patients with cardiovascular aging and diseases, we aim to provide a more detailed and updated review that reflects the advancements in the field of epigenetic modification in cardiovascular diseases.

Long-lasting persistence within infected cells is a major challenge for viral pathogens, as it necessitates an exact regulation of viral replication to reduce viral cytopathic effects. This is particularly challenging for viruses that persistently infect cells with limited renewal capabilities, such as neurons. Accordingly, neurotropic viruses have evolved various specific mechanisms to promote a long-lasting persistent infection in the host cells without inducing an exacerbated cytopathic effect. Borna disease virus (BDV) and Human immunodeficiency virus (HIV) are two neurotropic RNA viruses that, in contrast to other RNA viruses, can establish long-lasting intranuclear infections within the nervous system. These viruses interact with different cellular processes such as epigenetic modifications to develop a successful persistence infection. Studies show that cellular epigenetic mechanisms play a significant role in the pathogenesis of BDV and HIV and their neurological disorders. Hence, targeting these mechanisms by epigenetic modulator agents can be regarded as a novel therapeutic strategy to manage BDV- and HIV-associated neurological diseases. This review provides an overview of different epigenetic modulator compounds as a potential therapeutic target for controlling persistent neurotropic intranuclear infections caused by BDV and HIV.

In plants, cytosine DNA methylation (mC) is largely associated with transcriptional repression of transposable elements, but it can also be found in the body of expressed genes, referred to as gene body methylation (gbM). gbM is correlated with ubiquitously expressed genes; however, its function, or absence thereof, is highly debated. The different outputs that mC can have raise questions as to how it is interpreted-or read-differently in these sequence and genomic contexts. To screen for potential mC-binding proteins, we performed an unbiased DNA affinity pull-down assay combined with quantitative mass spectrometry using methylated DNA probes for each DNA sequence context. All mC readers known to date preferentially bind to the methylated probes, along with a range of new mC-binding protein candidates. Functional characterization of these mC readers, focused on the MBD and SUVH families, was undertaken by ChIP-seq mapping of genome-wide binding sites, their protein interactors, and the impact of high-order mutations on transcriptomic and epigenomic profiles. Together, these results highlight specific context preferences for these proteins, and in particular the ability of MBD2 to bind predominantly to gbM. This comprehensive analysis of Arabidopsis mC readers emphasizes the complexity and interconnectivity between DNA methylation and chromatin remodeling processes in plants.

Feather pecking (FP) is a repetitive behaviour in chickens, influenced by genetic, epigenetic, and environmental factors, similar to behaviours seen in human developmental disorders (e.g., hyperactivity, autism). This study examines genetic and neuro-epigenetic factors in the thalamus of chickens from lines selected for seven generations for high or low FP behaviour (HFP or LFP). We integrate data on Differentially Methylated Regions (DMRs), Single Nucleotide Polymorphisms (SNPs), and Copy Number Variations (CNVs) in this controlled artificial selection process. Significant differences in behaviour, immunology, and neurology have been reported in these lines. We identified 710 SNPs in these lines that indicate new potentially important genes for FP such as TMPRSS6 (implicated in autism), and SST and ARNT2 (somatostatin function). CNV were the omic level most affected during selection. The largest CNVs found were in RIC3 (gain in HFP) and SH3RF2 (gain in LFP) genes, linked to nicotinic acetylcholine receptor regulation and human oncogenesis, respectively. Our study also suggests that promoters and introns are hotspots for CpG depletion. The overlapping of the omic levels investigated here with data from a public FP Quantitative Trait Loci (QTL) database revealed novel candidate genes for understanding repetitive behaviours, such as RTKN2, associated with Alzheimer's disease in humans. This study suggests CNVs as a crucial initial step for genomic diversification, potentially more impactful than SNPs.

The complex relationship between kidney disease and hypertension represents a critical area of research, yet less attention has been devoted to exploring how this connection develops early in life. Various environmental factors during pregnancy and lactation can significantly impact kidney development, potentially leading to kidney programming that results in alterations in both structure and function. This early programming can contribute to adverse long-term kidney outcomes, such as hypertension. In the context of kidney programming, the molecular pathways involved in hypertension are intricate and include epigenetic modifications, oxidative stress, impaired nitric oxide pathway, inappropriate renin-angiotensin system (RAS) activation, disrupted nutrient sensing, gut microbiota dysbiosis, and altered sodium transport. This review examines each of these mechanisms and highlights reprogramming interventions proposed in preclinical studies to prevent hypertension related to kidney programming. Given that reprogramming strategies differ considerably from conventional treatments for hypertension in kidney disease, it is essential to shift focus toward understanding the processes of kidney programming and its role in the development of programmed hypertension.

Histone modification signatures mark sites of transcriptional regulatory elements and regions of gene activation and repression. These sites vary among cell types and undergo dynamic changes during development and in diseases. Oocytes produce numerous maternal factors essential for early embryonic development, which are significantly influenced by epigenetic modifications. The profiling of epigenetic modifications during oogenesis remains uniquely challenging due to the presence of numerous tightly wrapped granulosa cells. Here, we successfully established a low-input CUT&Tag (Cleavage Under Targets and Tagmentation) method tailored for zebrafish stage I oocytes. This advanced technique enables high-resolution profiling of histone modifications and DNA-binding proteins, critical for understanding chromatin dynamics in developing oocytes. In this study, we detailed the workflow for this technique, including the isolation of pure stage I oocytes without somatic cells, library construction and quality monitoring. Our results demonstrate the method's efficacy by identifying distinct histone modification patterns and analyzing differentially expressed genes in oocytes with and without granulosa cells. We also successfully profiled divergent histone modifications in oocytes derived from wild-type and huluwa mutants. These advancements overcome technical challenges in epigenetic research on zebrafish oocytes and establish a solid foundation for exploring the epigenetic regulatory mechanisms of maternal contribution.

An earlier study of ours investigating the effect of dietary lipid levels on the choline requirement of Atlantic salmon showed increasing severity of intestinal steatosis with increasing lipid levels. As choline is involved in epigenetic regulation by being the key methyl donor, pyloric caeca samples from the study were analysed for epigenetic effects of dietary lipid and choline levels. The diets varied in lipid levels between 16% and 28%, and choline levels between 1.9 and 2.3 g/kg. The diets were fed for 8 weeks to Atlantic salmon of 25 g of initial weight. Using reduced representation bisulfite sequencing (RRBS), this study revealed that increasing dietary lipid levels induced methylation differences in genes involved in membrane transport and signalling pathways, and in microRNAs important for the regulation of lipid homoeostasis. Increasing choline levels also affected genes involved in fatty acid biosynthesis and transport, lipolysis, and lipogenesis, as well as important immune genes. Our observations confirmed that choline is involved in epigenetic regulation in Atlantic salmon, as has been reported for higher vertebrates. This study showed the need for the inclusion of biomarkers of epigenetic processes in studies that must be conducted to define optimal choline levels in diets for Atlantic salmon.

There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.

Sjögren's syndrome (SS) is an autoimmune disease that can be classified as an epithelitis based on the immune-mediated attack directed specifically at epithelial cells. SS predominantly affects women, is characterized by the production of highly specific circulating autoantibodies, and the major targets are the salivary and lachrymal glands. Although a genetic predisposition has been amply demonstrated for SS, the etiology remains unclear. The recent integration of epigenetic data relating to autoimmune diseases opens new therapeutic perspectives based on a better understanding of the molecular processes implicated. In the autoimmune field, non-coding RNA molecules (nc-RNA), which regulate gene expression by binding to mRNAs and could have a therapeutic value, have aroused great interest. The focus of this review is to summarize the biological functions of nc-RNAs in the pathogenesis of SS and decode molecular pathways implicated in the disease, in order to identify new therapeutic strategies.

Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11i significantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK inhibitor momelotinib, HDAC inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.

Tuberculosis caused by the obligate intracellular pathogen, Mycobacterium tuberculosis, is one among the prime causes of death worldwide. An urgent remedy against tuberculosis is of paramount importance in the current scenario. However, the complex nature of this appalling disease contributes to the limitations of existing medications. The quest for better treatment approaches is driving the research in the field of host epigenomics forward in context with tuberculosis. The interplay between various host epigenetic factors and the pathogen is under investigation. A comprehensive understanding of how Mycobacterium tuberculosis orchestrates such epigenetic factors and favors its survival within the host is in increasing demand. The modifications beneficial to the pathogen are reversible and possess the potential to be better targets for various therapeutic approaches. The mechanisms, including histone modifications, DNA methylation, and miRNA modification, are being explored for their impact on pathogenesis. In this article, we are deciphering the role of mycobacterial epigenetic regulators on various strategies like cytokine expression, macrophage polarization, autophagy, and apoptosis, along with a glimpse of the potential of host-directed therapies.

DNA methylation (DNAm) has unique properties which makes it a potential biomarker for lifestyle-related exposures. Epigenetic clocks, particularly DNAm-based biological age predictors [epigenetic age (EA)], represent an exciting new area of clinical research and deviations of EA from chronological age [epigenetic age acceleration (EAA)] have been linked to overall health, age-related diseases, and environmental exposures.

This observational study investigates the relationships between biological aging and various dietary factors within the LifeLines-DEEP Cohort. These factors include diet quality, processed food consumption, dietary glycemic load, and intake of vitamins involved in maintaining the epigenetic homeostasis (vitamins B-9, B-12, B-6, B-2, and C).

Dietary records collected using food-frequency questionnaires were used to estimate diet quality [LifeLines Diet Score (LLDS)], measure the intake of unprocessed/ultraprocessed food according to the NOVA food classification system, and the adequacy of the dietary intake of vitamins B-9, B-12, B-2, B-6, and C. EA using Horvath, Hannum, Levine, and Horvath2 epigenetic clock models and DNAm-predicted telomere length (DNAm-TL) were calculated from DNAm data in 760 subjects. Associations between dietary factors and EAA were tested, adjusting for sex, energy intake, and body composition.

LLDS was associated with EAA (EAA_Horvath: β: -0.148; P = 1 × 10-4; EAA_Hannum: β: -0.148; P = 9 × 10-5; EAA_Levine: β: -0.174; P = 1 × 10-5; and EAA_Horvath2: β: -0.176; P = 4 × 10-6) and DNAm-TL (β: 0.116; P = 0.003). Particularly, EAA was associated with dietary glycemic load (EAA_Horvath: β: 0.476; P = 9 × 10-10; EAA_Hannum: β: 0.565; P = 1 × 10-13; EAA_Levine: β: 0.469; P = 5 × 10-9; EAA_Horvath2: β: 0.569; P = 1 × 10-13; and DNAmTL adjusted for age: β: -0.340; P = 2 × 10-5) and different measures of food processing (NOVA classes 1 and 4). Positive EAA was also associated with inadequate intake of vitamin B-12 (EAA_Horvath: β: -0.167; P = 0.002; EAA_Hannum: β: -0.144; P = 0.007; and EAA_Horvath2: β: -0.126; P = 0.019) and C (EAA_Hannum: β: -0.136; P = 0.010 and EAA_Horvath2: β: -0.151; P = 0.005).

Our findings corroborate the hypothesis that nutrition plays a pivotal role in influencing epigenetic homeostasis, especially DNAm, thereby contributing to individual health trajectories and the pace of aging.

Bisphenols are mainly used as protective coatings for plastics and resin-based materials in various consumer products. Industrial producers have a high demand for bisphenol A (BPA) among all bisphenol substitutes for various consumer products. However, according to reports, prolonged exposure to BPA can cause multiple health issues, including neurodevelopmental disorders in young children. BPA exposure during pregnancy has been considered as the primary cause of increasing the risk of neurological disorders in children as their neural systems are designed to respond to any environmental changes during prenatal life. Recently, there has been an increased focus on the effects of prenatal exposure to BPA, as it has been found to alter gene expression related to epigenetic mechanisms like DNA methylation, histone modification, and microRNA expression. Based on the evidence, frequent interactions can lead to inherited changes in an individual's neural profile. In this review, we delve into the current knowledge regarding the toxicity mechanism of BPA for expecting mothers. Next, we will discuss the possible action of BPA on the epigenetic mechanism during brain development. This is especially important to portray an overview on the role of epigenetic modification caused by prenatal BPA exposure and next, give future directions for improving human health risk assessment caused by BPA exposure.

The differential ratio of nonsynonymous to synonymous nucleotide substitutions (dN/dS) is a common measure of the rate of structural evolution in proteincoding genes. In addition, we recently suggested that the proportion of transposable elements in gene promoters that host functional genomic sites serves as a marker of the rate of regulatory evolution of genes. Such functional genomic regions may include transcription factor binding sites and modified histone binding loci.

Here, we constructed a model of the human interactome based on 600,136 documented molecular interactions and investigated the overall relationship between the number of interactions of each protein and the rate of structural and regulatory evolution of the corresponding genes.

By evaluating a total of 4,505 human genes and 1,936 molecular pathways we found a general correlation between structural and regulatory evolution rate metrics (Spearman 0.08-0.16 and 0.25-0.37 for gene and pathway levels, respectively, p < 0.01). Further exploration revealed in the established human interactome model lack of correlation between the rate of gene regulatory evolution and the number of protein interactions on gene level, and weak negative correlation (∼0.15) on pathway level. We also found a statistically significant negative correlation between the rate of gene structural evolution and the number of protein interactions (Spearman -0.11 and -0.3 for gene and pathway levels, respectively, p < 0.01).

Our result suggests stronger structural rather than regulatory conservation of genes whose protein products have multiple interaction partners.

HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.

Cancer is a leading cause of mortality worldwide. The evolving role of epigenetics and tumor microenvironments of cancer pose significant challenges to the management of cancer. Besides genetics, epigenetic changes play a crucial role in the alteration of cellular machinery, progression, metastasis, epithelial-mesenchymal transition, and chemoresistance. Epigenetic changes such as DNA and RNA methylation, histone modifications, and chromatin modeling directly or indirectly influence the different stages of cancer from initiation to chemoresistant phenotype. In addition, alterations in the epigenetic machinery, such as hypo- or hyperactivation of proteins involved in epigenetic modifications, can lead to different health complications, including cancer. Recently, epi-drugs or epigenetic drugs offer emerging hope for the treatment and management of this deadly disease. Various epigenetic drugs targeting factors responsible for epigenetic modifications in cancer are currently under clinical trials. This chapter provides an overview of epigenetic modifications, their clinical implications, and the potential of epigenetic drugs for cancer treatment.