Changes in chromatin accessibility caused by histone modifications regulate gene transcription. However, little is known about associations between gene expression changes caused by histone modifications and viral infections. We investigate the midguts of silkworms infected with Bombyx mori cypovirus (BmCPV) at 48 h and 96 h post infection (CPV48 and CPV96), and corresponding midguts of uninfected silkworms (GUT48 and GUT96) using CUT&Tag-seq and RNA-seq. We report H3K9me3, H3K9ac, and gene expression profiles at the genome-wide level to change with BmCPV infection. Differential H3K9me3 peak-related genes were mainly enriched in MAPK, Wnt, and Hippo signalling pathways; Differential H3K9ac peaks-related genes were mainly enriched in the Hippo signalling, apoptosis, and citrate cycle pathways; and differentially expressed genes (DEGs) were mainly enriched in carbon metabolism, protein processing in endoplasmic reticulum, and glycolysis/gluconeogenesis pathways. Integration analysis between H3K9me3/H3K9ac peaks and gene expression revealed changes in gene expression profiles to be associated with alteration of H3K9me3/H3K9ac at promoters; gene expression correlates negatively with corresponding H3K9me3 signals in gene bodies, and positively with corresponding H3K9ac signals at the transcription start site. Intersection genes with log2foldchange of both CUT&Tag-seq peak and RNA-seq FPKM > 1 were screened and annotated. Genes shared by differential H3K9me3 peak-related genes and DEGs were enriched in insect hormone biosynthesis, MAPK signalling, and TGF-beta signalling pathways, and genes shared by differential H3K9ac peak-related genes and DEGs were enriched in glycolysis/gluconeogenesis, TGF-beta signalling, and mitophagy pathways. These results indicate that BmCPV regulates gene expression through H3K9me3/H3K9ac.

Lactylation, a recently identified posttranslational modification (PTM), has emerged as a critical regulatory mechanism in cardiovascular diseases (CVDs). This PTM involves the addition of lactyl groups to lysine residues on histones and nonhistone proteins, influencing gene expression and cellular metabolism. The discovery of lactylation has revealed new directions for understanding metabolic and immune processes, particularly in the context of CVDs. This review describes the intricate roles of specific lactylated proteins and enzymes, such as H3K18, HMGB1, MCT1/4, and LDH, in the regulation of cardiovascular pathology. This study also highlights the unique impact of lactylation on myocardial hypertrophy and distinguishes it from other PTMs, such as SUMOylation and acetylation, underscoring its potential as a therapeutic target. Emerging drugs targeting lactate transporters and critical enzymes involved in lactylation offer promising avenues for novel CVD therapies. This review calls for further research to elucidate the mechanisms linking lactylation to CVDs, emphasizing the need for comprehensive studies at the molecular, cellular, and organismal levels to pave the way for innovative preventive, diagnostic, and treatment strategies in cardiovascular medicine.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss and functional decline, posing significant global health challenges. Emerging evidence highlights nicotinamide N-methyltransferase (NNMT), a cytosolic enzyme regulating nicotinamide (NAM) methylation, as a pivotal player in NDs through its dual impact on epigenetic regulation and metabolic homeostasis. This review synthesizes current knowledge on NNMT's role in disease pathogenesis, focusing on its epigenetic modulation via DNA hypomethylation and histone modifications, alongside its disruption of NAD+ synthesis and homocysteine (Hcy) metabolism. Elevated NNMT activity depletes NAD+, exacerbating mitochondrial dysfunction and impairing energy metabolism, while increased Hcy levels drive oxidative stress, neuroinflammation, and aberrant protein aggregation (e.g., Aβ, tau, α-synuclein). Notably, NNMT overexpression in AD and PD correlates with neuronal hypomethylation and neurotoxicity, as observed in postmortem brain studies and transgenic models. Mechanistically, NNMT consumes S-adenosylmethionine (SAM), limiting methyl donor availability for DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), thereby altering gene expression patterns critical for neuronal survival. Concurrently, NNMT-mediated NAD+ depletion disrupts sirtuin activity (e.g., SIRT1) and mitochondrial biogenesis, accelerating axonal degeneration. Therapeutic strategies targeting NNMT, such as RNA interference (RNAi), small-molecule inhibitors and exercise therapy, show promise in preclinical models by restoring NAD+ levels and reducing Hcy toxicity. However, challenges persist in achieving cellular specificity, optimizing blood-brain barrier penetration, and mitigating off-target effects. This review underscores NNMT's potential as a multifactorial therapeutic target, bridging metabolic and epigenetic dysregulation in NDs. Future research should prioritize elucidating tissue-specific NNMT interactions, refining inhibitor pharmacokinetics, and validating translational efficacy in clinical trials. Addressing these gaps could pave the way for novel disease-modifying therapies to combat the rising burden of neurodegeneration.

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

Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases. In CD8⁺ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4⁺ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism. Therefore, understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations. This review explores the interplay between DNA methylation, histone alterations, and metabolic changes underlying T cell aging.

Glycosylation, a key post-translational modification, plays a pivotal role in cancer progression by influencing critical processes such as protein folding, immune modulation, and intercellular signaling. Altered glycosylation patterns are increasingly recognized as fundamental drivers of tumorigenesis, contributing to key cancer hallmarks like enhanced tumor migration, metastasis, and immune evasion. These aberrant glycosylation signatures not only offer insights into cancer biology but also serve as valuable diagnostic markers and potential therapeutic targets across a range of malignancies. This review explores the mechanisms underlying glycosylation alterations in cancer. We discuss the molecular basis of these changes, including genetic mutations, epigenetic regulation, and oncogene-driven shifts in glycosylation pathways. Additionally, we highlight recent advancements in glycomics research, with a focus on how these alterations influence tumor progression, angiogenesis, and the tumor microenvironment. Furthermore, the review considers the clinical implications of glycosylation changes, including their role in resistance to anti-cancer therapies and their potential as biomarkers for personalized treatment strategies. By bridging fundamental glycosylation research with clinical applications, this review underscores the promise of glycosylation as both a diagnostic tool and a therapeutic target in oncology, offering new avenues for improved patient stratification and precision medicine.

Cancer stem cells (CSCs) are a subpopulation with self-renewal and differentiation capacities believed to be responsible for tumor initiation, progression, and recurrence. These cells exhibit unique metabolic features that contribute to their stemness and survival in hostile tumor microenvironments. Like non-stem cancer cells, CSCs primarily rely on glycolysis for ATP production, akin to the Warburg effect. However, CSCs also show increased dependence on alternative metabolic pathways, such as oxidative phosphorylation (OXPHOS) and fatty acid metabolism, which provide necessary energy and building blocks for self-renewal and therapy resistance. The metabolic plasticity of CSCs enables them to adapt to fluctuating nutrient availability and hypoxic conditions within the tumor. Recent studies highlight the importance of these metabolic shifts in maintaining the CSC phenotype and promoting cancer progression. The CSC model suggests that a small, metabolically adaptable subpopulation drives tumor growth and therapy resistance. CSCs can switch between glycolysis and mitochondrial metabolism, enhancing their survival under stress and dormant states. Targeting CSC metabolism offers a promising therapeutic strategy; however, their adaptability complicates eradication. A multi-targeted approach addressing various metabolic pathways is essential for effective CSC elimination, underscoring the need for further research into specific CSC markers and mechanisms that distinguish their metabolism from normal stem cells for successful therapeutic intervention.

Skin cancer prevalence has increased during the last decades, with the last years serving as a pivotal moment for comprehending its epidemiological patterns and its impact on public health. Melanoma is one of the most frequently occurring malignancies, arising from a complex interplay of genetic factors, environmental factors, lifestyle and socio-economic conditions. Epigenetic changes play a critical role in tumor development, influencing progression and aggressiveness. Epigenetic therapies could represent novel therapeutic options, while drug repositioning may serve as a viable strategy for cancer treatment. Demethylating agents, commonly used in hematological malignancies, show promising results on solid tumors, including melanoma. Methylation patterns are responsible for tumor development by modulating gene expression, while histone acetylation influences DNA processes such as transcription, replication, repair, and recombination. This review aims to identify existing potential therapeutical approaches using therapeutic agents that can modulate DNA methylation and histone modification, which can lead to tumor inhibition, cell death initiation and reactivation of tumor suppressor genes.

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation.

Structurally novel inhibitors of the lysine methyltransferase G9a have attracted considerable interest as potential drug candidates for cancer and genetic diseases. Here, a detailed account of potency optimization from early leads 8 and 9 to compound 16g is presented. Our search for an alternative scaffold for the 4-oxo-4,5,6,7-tetrahydro-1H-indole moiety of compounds 8 and 9 via parallel synthesis led to the identification of the 4-pyridin-4-ylamino phenyl substructure in compound 16g. This substructure was found to bind to the enzyme in a horizontally flipped manner compared with compound 8 in X-ray crystallographic analysis. Compound 16g is a highly potent G9a inhibitor (IC50 = 0.0020 μM) and structurally distinct from other G9a inhibitors reported in the literature. Importantly, compound 16g exhibited dose-dependent induction of γ-globin mRNA in HUDEP-2, leading to elevated γ-globin protein levels and F cell numbers in CD34+ bone marrow (BM)‒derived hematopoietic cells. Kinetic studies using surface plasmon resonance (SPR) analysis suggested that compound 16g interacts with G9a via a unique binding mode, as indicated by the markedly higher dissociation constant (KD) compared to those of compounds 8 and 9. Interestingly, X-ray crystallographic studies revealed that the binding motif of compound 16g was quite different from our previous series, including RK-701, and somewhat resembles that of endogenous substrates. Insights obtained in this lead optimization exercise on the association/dissociation constants as well as the binding motifs are expected to help in designing future G9a inhibitors for the treatment of sickle cell disease.

This book chapter will focus on modifications to chromatin itself, how chromatin modifications are regulated, and how these modifications are deciphered by the cell to impact aging. In this chapter, we will review how chromatin modifications change with age, examine how chromatin-modifying enzymes have been shown to regulate aging and healthspan, discuss how some of these epigenetic changes are triggered and how they can regulate the lifespan of the individual and its naïve descendants, and speculate on future directions for the field.

Methylation levels of core histones play important roles in the regulation of gene expression and impact animal development. However, the methyltransferases and demethylases that determine histone methylation levels remain largely unexplored in insects. Most of our current understanding of histone methylation comes from mammalian studies. In this study, we first identified potential histone methyltransferases and demethylases encoded in the genome of the red flour beetle Tribolium castaneum. The function of these histone methylation enzymes in the metamorphosis was investigated by knocking down genes coding for these enzymes using RNA interference (RNAi). Our results showed that a lysine methyltransferase, KMT5A, plays a critical role in T. castaneum metamorphosis by regulating the biosynthesis of ecdysteroids. Treating KMT5A-knockdown larvae with 20 hydroxyecdysone can partially rescue T. castaneum pupation. Western blot analysis showed that KMT5A catalyzes H4K20 mono-methylation. However, further studies suggest that KMT5A may regulate T. castaneum pupation through mechanisms independent of H4K20 methylation. These data uncovered the roles of histone methylation enzymes in T. castaneum metamorphosis and KMT5A as a critical regulator of ecdysteroid biosynthesis.

Histone lysine demethylase 5 (KDM5) is a ketoglutarate-dependent dioxygenase in histone lysine demethylation, playing a vital role in immunological memory by modulating H3K4me3. Investigating on the role of invertebrate KDM5 in the immune priming, a novel form of immunological memory recently verified in invertebrates, will further our knowledge of epigenetic regulation for innate immune memory. In the present study, a KDM5A was identified in Pacific oyster Crassostrea gigas, and its role in regulating haemocyte proliferation during immune priming was assessed. The deduced amino acid sequence of CgKDM5A harbors a complete JmjC domain featuring a conserved αKG binding site. The mRNA expression of CgKDM5A in the haemolymph was significantly higher than that in the tested tissues of the mature oysters. After Vibrio splendidus stimulation, CgKDM5A transcripts and KDM5 enzymatic activity in haemocytes significantly decreased, accompanying with increased H3K4me3 levels. Moreover, H3K4me3 modifications at the CgBMP7 and CgGATA2/3 promoters were elevated at 7 d after V. splendidus stimulation (p < 0.05), and the haemocyte proliferation index increased significantly at 12 h after the secondary stimulation (p < 0.05). Treatment with KDM5 activator DM-αKG further led to a significant increase in H3K4me3 enrichment levels at the CgBMP7 and CgGATA2/3 promoters at 7 d after the primary stimulation (p < 0.05). Subsequently, the expression of CgBMP7 and CgGATA2/3, as well as the haemocyte proliferation index decreased significantly after the secondary stimulation (p < 0.05). In contrast, CgKDM5A-RNAi oysters exhibited an enriched H3K4me3 at the CgBMP7 and CgGATA2/3 promoters at 7 d after the primary stimulation and an increased haemocyte proliferation index at 12 h after the secondary stimulation (p < 0.05). These findings suggest that CgKDM5A plays a critical role in haemocyte proliferation by affect H3K4me3 enrichment at the CgBMP7 and CgGATA2/3 promoters during immune priming in C. gigas, highlighting the potential of epigenetic regulation in innate immune memory of mollusks.

This review provides a comprehensive overview of the role of G9a/EHMT2, focusing on its structure and exploring the impact of its pharmacological and/or gene inhibition in various neurological diseases. In addition, we delve into the advancements in the design and synthesis of G9a/EHMT2 inhibitors, which hold promise not only as a treatment for neurodegeneration diseases but also for other conditions, such as cancer and malaria. Besides, we presented the discovery of dual therapeutic approaches based on G9a inhibition and different epigenetic enzymes like histone deacetylases, DNA methyltransferases, and other lysine methyltransferases. Hence, findings offer valuable insights into developing novel and promising therapeutic strategies targeting G9a/EHMT2 for managing these neurological conditions.

Prostate cancer is one of the most prevalent malignancies globally. This cancerous condition originates within the prostate gland, an integral part of the male reproductive system. The molecular mechanism underlying cancer is among the key areas of research in the scientific community. Cancer, being a multifactorial disease, is controlled by many factors ranging from environmental to genetic to epigenetic factors. Epigenetic regulation holds a crucial role in tumorigenesis and its progression. Epigenetics refers to alterations in the genome that happen without any changes to the DNA sequence itself; they may be triggered by multiple factors ranging from environmental to dietary factors. It includes methylation of DNA and histone modifications. Histone modifications, including histone methylation, histone acetylation, and histone ubiquitination, play a crucial role in the pathogenesis and progression of prostate cancer. These epigenetic modifications via transcriptional regulation affect key cellular processes and are thus implicated in prostate cancer and other cancers. These epigenetic markers could be used as both diagnostic and prognostic markers and also could be used as novel therapeutic targets against prostate cancer and other malignancies. Here in this review article, we have summarized different histone modifications and their mechanistic and therapeutic implications in prostate cancer.

Manifold biological processes at all levels of transcription and translation can lead to the formation of a high number of different protein species (i.e., proteoforms), which outnumber the sequences encoded in the genome by far. Due to the large number of protein molecules formed in this way, which span an enormous range of different physicochemical properties, proteoforms are the functional drivers of all biological processes, creating the need for powerful analytical approaches to decipher this language of life. While bottom-up proteomics has become the most widely used approach, providing features such as high sensitivity, depth of analysis, and throughput, it has its limitations when it comes to identifying, quantifying, and characterizing proteoforms. In particular, the major bottleneck is to assign peptide-level information to the original proteoforms. In contrast, top-down proteomics (TDP) targets the direct analysis of intact proteoforms. Despite being characterized by a number of technological challenges, the TDP community has established numerous protocols that allow easy implementation in any proteomics laboratory. In this viewpoint, we compare both approaches, argue that it is worth embedding TDP experiments, and show fields of research in which TDP can be successfully implemented to perform integrative multi-level proteoformics.

The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which dynamically interact with tumor cells to influence their behavior. Immunosuppression is a key feature of the OSCC TME, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contributing to an environment that allows tumor cells to evade immune surveillance and supports angiogenesis. The oral microbiome also plays a pivotal role in OSCC pathogenesis, as dysbiosis, or imbalances in the microbiota, can lead to chronic inflammation, which promotes carcinogenesis through the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Pathogens like Porphyromonas gingivalis and Fusobacterium nucleatum have, hence, been implicated in OSCC-driven tumor progression, as they induce inflammation, activate oncogenic pathways, and modulate immune responses. In this review, we discuss how the interplay between immunosuppression and microbiome-driven inflammation creates a tumor-promoting environment in OSCC, leading to treatment resistance and poor patient outcomes, and explore the potential therapeutic implication of a better understanding of OSCC etiology and molecular changes.

Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, presents significant public health challenges due to its genetic instability and late-stage diagnosis. Despite advancements in treatment, the median overall survival remains below one year, emphasizing the need for improved detection, prognosis, and therapeutic strategies. This study investigates the role of KDM4C and its interaction with GATA1 in regulating heme metabolism and tumor progression in HNSCC. KDM4C knockdown (KDM4C-KD) hindered HNSCC cell migration using in vitro assays, inhibited metastasis through zebrafish xenotransplantation, and suppressed tumor growth in mouse xenograft models. RNA-seq and CUT&Tag-seq analyses on KDM4C-KD SAS cells identified KDM4C-regulated genes, including ferrochelatase (FECH), in heme metabolism. Immunoprecipitation and docking analyses confirmed the KDM4C-GATA1 interaction. Notably, FECH overexpression in KDM4C or GATA1 knockdown cells restored cell migration, invasion, and proliferation, highlighting FECH as a crucial downstream target. KDM4 inhibitors myricetin and BPRKD022S0 (22S0) increased H3K9me3 levels, downregulated heme metabolism genes, and reduced cell survival in HNSCC cells. Zebrafish and mouse models demonstrated that these inhibitors effectively suppressed tumor growth and metastasis. Immunohistochemical analysis of HNSCC patient samples revealed high KDM4C and GATA1 expression correlated with advanced clinical stages and poor survival outcomes. Our findings elucidate the critical role of the KDM4C/GATA1-FECH axis in HNSCC progression and suggest that targeting this pathway with KDM4 inhibitors shows promising therapeutic potential for HNSCC treatment.

Endometrial function, crucial for successful embryo implantation, is significantly influenced by epigenetic regulation. This review investigates the crucial roles of DNA methylation, histone modifications, chromatin remodeling, and RNA methylation in endometrial receptivity and implantation, based on a survey of recent literature on knockout mouse models with implantation defects. These models illuminate how epigenetic disruptions contribute to implantation failure, a significant human reproductive health concern. DNA methylation and histone modifications modulate endometrial receptivity by affecting gene silencing and chromatin structure, respectively. Chromatin remodeling factors also play a critical role in endometrial dynamics, influencing gene expression. Furthermore, RNA methylation emerges as critical in implantation through transcriptional and translational control. While human studies provide limited epigenetic snapshots, mouse models with suppressed epigenetic regulators reveal direct causal links between epigenetic alterations and implantation failure. Understanding these epigenetic interactions offers potential for novel therapies addressing reproductive disorders.

Prostate cancer (PCa) is the second most common malignant tumor in men worldwide, particularly castration-resistant prostate cancer (CRPC), for which enzalutamide (Enz) resistance is of particular concern. Modifications to histone methylation and acetylation patterns are closely associated with resistance to Enz in these patients. As PCa progresses, cancer cells alter their histone modification patterns, leading to a reduction in Enz treatment efficacy. Signaling pathways in the tumor microenvironment regulate gene expression by affecting the activity of histone-modifying enzymes, further affecting the efficacy of Enz. This review summarizes recent research about changes in histone modification patterns that occur in drug resistance-related genes at different stages of PCa and explores the potential use of combination therapies for reversing this process, providing insights into novel treatment strategies to improve the clinical efficacy of Enz.

Skeletal muscle development is a complex biological process regulated by many factors, such as transcription factors, signaling pathways, and epigenetic modifications. Histone modifications are important epigenetic regulatory factors involved in various biological processes, including skeletal muscle development, and play a crucial role in the pathogenesis of skeletal muscle diseases. Histone modification regulators affect the expression of many genes involved in skeletal muscle development and disease by adding or removing certain chemical modifications. In this review, we comprehensively summarize the functions and regulatory activities of the histone modification regulators involved in skeletal muscle development, regeneration, and disease.

Using millions of methylation segments, we developed DiffuCpG, a generative artificial intelligence (AI) diffusion model designed to solve the critical challenge of missing data in high-throughput methylation technologies. DiffuCpG goes beyond conventional methods by leveraging both short-range interactions including nearby CpGs from both latitude and longitude of the dataset, local DNA sequences, and long-range interactions, including three-dimensional genome architecture and long-distance correlations, to comprehensively model the methylome. Compared to previous methods, through extensive independent validations across different tissue types, cancers, and technologies (whole-genome bisulfite sequencing, enhanced reduced representation bisulfite sequencing, single-cell bisulfite sequencing, and methylation arrays), DiffuCpG has demonstrated superior performance in accuracy, scalability, and versatility. On average, bisulfite sequencing dataset, DiffuCpG can extend the original dataset by millions of additional CpGs. As an alternative application of generative AI, DiffuCpG addresses a key bottleneck in epigenetic research and will substantially benefit studies relying on high-throughput methylation data.

Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, are influenced by environmental factors and play a central role in the progression and therapeutic targeting of kidney diseases, such as diabetic kidney disease (DKD), chronic kidney disease (CKD), and hypertension. These epigenetic changes are also preserved as cellular memory, with this "epigenetic memory" known to have long-term effects on such chronic diseases. Histone modifications are readily reversible epigenetic changes that regulate gene expression by altering chromatin structure or providing docking sites for transcriptional regulators. From a disease perspective, the involvement of epigenetics and "epigenetic memory" in DKD, CKD, senescence, and hypertension has been increasingly studied in recent years. Targeting epigenetic mechanisms is, thus, expected to offer novel therapeutic strategies for these diseases. Advances in treatment include histone deacetylase inhibitors and methyltransferase inhibitors, their applications of which have expanded from oncology to nephrology. However, challenges such as long-term toxicity and off-target effects remain significant. Further elucidation of kidney-specific epigenetic pathways and memory mechanisms may pave the way for precision epigenetic therapies, enabling the reversal of pathological epigenetic signatures and the mitigation of disease progression.

This review integrates recent advancements, highlighting functional evidence that histone modifications, particularly histone tail methylation, are involved in the pathogenesis of kidney diseases. It also emphasizes the translational significance of these findings, underlining the potential of epigenetics-based therapies to transform the management of kidney diseases.

Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Post-translational modifications (PTMs) on histones play a crucial role in determining the structure and function of chromatin, thereby regulating the eukaryotic gene expression. Histone lysine methylation and acetylation are among the most widespread and biomedically important PTMs, with new chemical tools for their examination in high demand. Here, we report the first use of γ-selenalysine as an efficient lysine mimic for enzymatic methylation, acetylation, and deacetylation reactions catalyzed by histone lysine methyltransferases, acetyltransferases, and a deacetylase. We also show that easily accessible selenocysteine and cysteine residues can undergo chemo- and site-selective alkylation reactions to generate both unmodified and modified γ-selenalysine and related γ-thialysine residues in histone peptides. This dual-modification strategy enables the site-specific incorporation of two distinct functionalities into peptides, mimicking lysine post-translational modifications commonly found on histones. Our research presents a novel approach in which selenocysteine serves as a unique handle for the chemoselective introduction of selenalysine, along with its methylated and acetylated analogues. These tools are designed to facilitate the study of epigenetic proteins that are important for human health and disease.

Cardiovascular diseases are the leading causes of death worldwide. However, there are still shortcomings in the currently employed treatment methods for these diseases. Therefore, exploring the molecular mechanisms underlying cardiovascular diseases is an important avenue for developing new treatment strategies. Previous studies have confirmed that metabolic and epigenetic alterations are often involved in cardiovascular diseases across patients. Moreover, metabolic and epigenetic factors interact with each other and affect the progression of cardiovascular diseases in a coordinated manner. Lactylation is a novel posttranslational modification (PTM) that links metabolism with epigenetics and affects disease progression. Therefore, analyzing the crosstalk between cellular metabolic and epigenetic factors in cardiovascular diseases is expected to provide insights for the development of new treatment strategies. The purpose of this review is to describe the relationship between metabolic and epigenetic factors in heart development and cardiovascular diseases such as heart failure, myocardial infarction, and atherosclerosis, with a focus on acylation and methylation, and to propose potential therapeutic measures.

Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by elevated pulmonary vascular resistance and pulmonary artery pressure, resulting from a multitude of etiological factors. If left untreated, PAH progressively leads to right heart failure and is associated with high mortality. The etiology of PAH is multifactorial, encompassing both congenital genetic predispositions and acquired secondary influences. Epigenetics, which refers to the regulation of gene expression through chromosomal alterations that do not involve changes in the DNA sequence, has garnered significant attention in PAH research. This includes mechanisms such as DNA methylation, histone modification, and RNA modification. Aberrant epigenetic modifications have been closely linked to the dysregulated proliferation and apoptosis of pulmonary artery smooth muscle cells and endothelial cells, suggesting that these alterations may serve as pivotal drivers of the pathophysiological changes observed in PAH. This review examines the potential impact of epigenetic alterations on the pathogenesis of PAH, highlighting their promise as therapeutic targets. Furthermore, we explore emerging therapeutic strategies and compounds aimed at modulating these epigenetic markers, and discusses their potential applications in both preclinical models and clinical trials. As our understanding of epigenetics deepens, it holds the potential to unlock novel avenues for the precise, individualized treatment of PAH, offering a new frontier in the fight against this debilitating disease.

Adult neurogenesis is a unique cellular process of the ongoing generation of new neurons throughout life, which primarily occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. In the adult DG, newly generated granule cells from neural stem cells (NSCs) integrate into existing neural circuits, significantly contributing to cognitive functions, particularly learning and memory. Recently, more and more studies have shown that rather than being a homogeneous population of identical cells, adult NSCs are composed of multiple subpopulations that differ in their morphology and function. In this study, we provide an overview of the origin, regional characteristics, prototypical morphology, and molecular factors that contribute to NSC heterogeneity. In particular, we discuss the molecular mechanisms underlying the balance between activation and quiescence of NSCs. In summary, this review highlights that deciphering NSC heterogeneity in the adult brain is a challenging but critical step in advancing our understanding of tissue-specific stem cells and the process of neurogenesis in the adult brain.

Advancements in genome sequencing technologies have uncovered the multifaceted roles of long non-coding RNAs (lncRNAs) in human cells. Recent discoveries have identified lncRNAs as major players in gene regulatory pathways, highlighting their pivotal role in human cell growth and development. Their dysregulation is implicated in the onset of genetic disorders and age-related diseases, including cancer. Specifically, they have been found to orchestrate molecular mechanisms impacting epigenetics, including DNA methylation and hydroxymethylation, histone modifications, and chromatin remodeling, thereby significantly influencing gene expression. This review provides an overview of the current knowledge on lncRNA-mediated epigenetic regulation of gene expression, emphasizing the biomedical implications of lncRNAs in the development of different types of cancers and genetic diseases.

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies.

Over the last decades, messenger RNA (mRNA) has emerged as a promising therapeutic modality, enabling the delivery of genetic instructions to cells for producing therapeutic proteins or antigens. As such, mRNA-based therapies can be developed for a wide range of conditions, including infections, cancer, metabolic disorders, and genetic diseases. Nevertheless, using mRNA therapeutically requires chemical modifications to reduce immunostimulatory effects and nanotechnology to prevent degradation and ensure intracellular delivery. Lipid nanoparticles (LNPs) have become the most effective delivery platform for mRNA therapeutics, which are primarily employed for vaccine purposes following local administration and hepatic applications following systemic administration. Here, we review the state-of-the-art LNP-mRNA technology and discuss its potential for immunotherapy. We first outline the requirements for mRNA to be used therapeutically, including the role of LNP-mediated delivery. Next, we highlight LNP-mRNA immunotherapy approaches for vaccination, immuno-oncology, and autoimmune disorders. In addition, we discuss challenges that are limiting LNP-mRNA's widespread use, including tunable biodistribution and immunostimulatory effects. Finally, we provide an outlook on how implementing approaches such as library screening and machine learning will guide the development of next-generation mRNA therapeutics.

Landmark studies at the turn of the century revealed metabolic reprogramming as a driving force for lymphocyte differentiation and function. In addition to metabolic changes, differentiating lymphocytes must remodel their epigenetic landscape to properly rewire their gene expression. Recent discoveries have shown that metabolic shifts can shape the fate of lymphocytes by altering their epigenetic state, bringing together these two areas of inquiry. The ongoing evolution of high-dimensional cytometry has enabled increasingly comprehensive analyses of metabolic and epigenetic landscapes in lymphocytes that transcend the technical limitations of the past. Here, we review recent insights into the interplay between metabolism and epigenetics in lymphocytes and how its dysregulation can lead to immunological dysfunction and disease. We also discuss the latest technical advances in cytometry that have enabled these discoveries and that we anticipate will advance future work in this area.

Head and neck squamous cell carcinoma (HNSCC) is one of the deadliest human cancers, with the overall 5-year survival rate stagnating in recent decades due to the lack of innovative treatment approaches. Apart from the recently Food and Drug Administration-approved epidermal growth factor receptor inhibitor and immune checkpoint inhibitor, alternative therapeutic strategies that target epigenetic abnormalities, an emerging cancer hallmark, remain to be fully explored. A pathological epigenetic landscape, characterized by widespread reprogramming of chromatin modifications such as DNA methylation and histone modifications, which drives transcription deregulation and genome reorganization, has been extensively documented in numerous cancers, including HNSCC. Growing evidence indicates that these frequent epigenomic alterations play pivotal roles in regulating malignant transformation, promoting metastasis and invasion, and reshaping the tumor microenvironment. Furthermore, these epigenetic changes also present unique vulnerabilities that open new avenues for identifying novel prognostic biomarkers and developing targeted antitumor therapies. In this review, we summarize recent discoveries of epigenetic dysregulations in HNSCC, with a focus on deregulated chromatin modifications, which include aberrant DNA methylation, oncohistone H3 lysine 36 to methionine (H3K36M) mutation, as well as recurrent mutations or altered expression of chromatin-modifying enzymes such as NSD1, EZH2, and KMT2C/D. Importantly, we discuss the various molecular mechanisms underlying the contributions of these epigenetic alterations to HNSCC development, particularly their involvement in deregulated cell proliferation and cell death, metabolic reprogramming, tumor immune evasion, and phenotypic plasticity. Finally, we conclude by highlighting the translational and clinical implications of targeting the epigenetic machinery, which offers promising prospects for overcoming resistance to conventional radiotherapy/chemotherapy and enhancing the response to immunotherapy in HNSCC.

Lysine-specific demethylase 1 (LSD1) is a key enzyme that removes the methylation marks from lysines in the histone tails of nucleosomes. Emerging evidence suggests that LSD1 exhibits both enzyme-dependent and independent functions across various diseases. However, most LSD1-targeted therapies in clinical trials focus on its classic demethylase activity. Only one allosteric inhibitor (SP-2577) and two nonproteolysis-targeting chimera (PROTAC) LSD1 degraders (BEA-17 and UM171), which target its enzyme-independent functions, have entered clinical assessment. Given the limited exploration of therapeutic strategies targeting the non-enzymatic functions of LSD1, in this opinion, we summarize current insights into its biological roles and structural characteristics. We also highlight potential therapeutic interventions targeting the non-enzymatic functions of LSD1, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and small-molecule degraders, and discuss challenges and future directions in drug discovery targeting these functions.

Suicide continues to be a significant public health issue globally, claiming over 700,000 lives annually. It is, therefore, important to assess the suicide risk properly and provide intervention in a timely fashion. While the heritability of suicidal behavior is around 50%, it does not explain the factors involved in causality. Recent evidence suggests that gene x environment interaction plays a vital role in suicidal behavior. In this paper, we critically evaluate the association between adolescent suicidal behavior and epigenetic modifications, including DNA methylation, histone modification, and non-coding RNAs, as well as epigenetic-based treatment options. It was noted that the prevalence of suicidal behavior in adolescents varied by age and sex and the presence of psychiatric disorders. Childhood adversity was closely associated with suicidal behavior. Studies show that alterations in epigenetic modifications may increase the risk of suicidal behavior independent of mental illnesses. Because epigenetic factors are reversible, environmental enrichment or the use of pharmacological agents that can target specific epigenetic modulation may be able to reduce suicidal behavior in this population.

Metabolic pathways exhibit fluctuating activities during bone and dental loss and defects, suggesting a regulated metabolic plasticity. Skeletal remodeling is an energy-demanding process related to altered metabolic activities. These metabolic changes are frequently associated with epigenetic modifications, including variations in the expression or activity of enzymes modified through epigenetic mechanisms, which directly or indirectly impact cellular metabolism. Metabolic reprogramming driven by bone and dental conditions alters the epigenetic landscape by modulating the activities of DNA and histone modification enzymes at the metabolite level. Epigenetic mechanisms modulate the expression of metabolic genes, consequently influencing the metabolome. The interplay between epigenetics and metabolomics is crucial in maintaining bone and dental homeostasis by preserving cell proliferation and pluripotency. This review, therefore, aims to examine the effects of metabolic reprogramming in bone and dental-related cells on the regulation of epigenetic modifications, particularly acetylation, methylation, and lactylation. We also discuss the effects of chromatin-modifying enzymes on metabolism and the potential therapeutic benefits of dietary compounds as epigenetic modulators. In this review, we highlight the inconsistencies in current research findings and suggest potential approaches to translate fundamental insights into clinical treatments for bone and tooth diseases.

S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms. This suggests that the need to maintain SAM homeostasis represents a significant evolutionary pressure across all kingdoms of life. Here, we review how SAM controls cellular functions at the molecular level and discuss strategies to maintain SAM homeostasis. We propose that SAM exerts a broad and underappreciated influence in cellular regulation that remains to be fully elucidated.

Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.

Genetic and epigenetic modifications of DNA are involved in cancer initiation and progression. Epigenetic modifications change chromatin structure and DNA accessibility and thus affect DNA replication, DNA repair and transcription. Epigenetic modifications are reversible and include DNA methylation, histone acetylation and histone methylation. DNA methylation is catalysed by DNA methyltransferases, histone acetylation and deacetylation are catalysed by histone acetylases and deacetylases, while histone methylation is catalysed by histone methyltransferases. Epigenetic modifications are dysregulated in several cancers, making them cancer therapeutic targets. Epigenetic drugs (epi-drugs) which are inhibitors of epigenetic modifications and include DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi) and bromodomain and extra-terminal motif protein inhibitors (BETi), have demonstrated clinical success as anti-cancer agents. Furthermore, the combination of epi-drugs with standard chemotherapeutic agents has demonstrated promising anti-cancer effects in pre-clinical and clinical settings. In this review, we discuss the role of epi-drugs in cancer therapy and explore their current and future use in combination with other anti-cancer agents used in the clinic. We further highlight the side effects and limitations of epi-drugs. We additionally discuss novel delivery methods and novel tumour epigenetic biomarkers for the screening, diagnosis and development of personalised cancer treatments, in order to reduce off-target toxicity and improve the specificity and anti-tumour efficacy of epi-drugs.

The global aging trend has posed significant challenges, rendering healthcare for older adults a crucial focus in medical research. Among the numerous health concerns related to aging, vascular aging and dysfunction are important risk factors and underlying causes of age-related diseases. Histone methylation and demethylation, which are involved in gene expression and cellular senescence, are closely associated with the occurrence and development of vascular aging. Consequently, this review aimed to identify the role of histone methylation in the pathogenesis of vascular aging and its potential for treating age-related vascular diseases and provided new insights into therapeutic strategies targeting the vascular system.

Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.

Long-term nephrocalcinosis leads to kidney injury, fibrosis, and even chronic kidney disease (CKD). Macrophage-to-myofibroblast transition (MMT) has been identified as a new mechanism in CKD, however, the effect of MMT in calcium oxalate (CaOx)-induced kidney fibrosis remains unclear. In this study, abundant MMT cells are identified by immunofluorescence (IF) and flow cytometry in kidney tissues of patients with CaOx-related CKD, a male mouse model, and CaOx-treated macrophages. Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice. Transcriptomic sequencing reveals that histone methyltransferase (HMTs), EZH2, is highly expressed in nephrocalcinosis. Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis. Mechanistically, ChIP and transcriptomic sequencing show that EZH2 inhibition reduces the enrichment of H3K27me3 on the Dusp23 gene promoter and elevates Dusp23 expression. The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis.