Search Results (393)

The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a conserved transcriptional coactivator that coordinates histone modifications and transcriptional regulation in eukaryotes. In Cryptococcus neoformans, SAGA governs key virulence traits, yet the roles of several core scaffold subunits remain undefined. Here, we characterize the functional roles of Spt7, a core SAGA component, in C. neoformans. Comparative genomics revealed that C. neoformans Spt7 retains conserved histone fold and bromodomain motifs. Deletion of SPT7 produced pleiotropic phenotypes, including defective melanization and capsule formation, impaired titan cell development, and heightened sensitivity to thermal, metal, antifungal, and cell wall stresses. The spt7Δ mutant exhibited strong sensitivity to the echinocandin micafungin, implicating Spt7 in maintaining cell wall integrity. The spt7Δ mutant was avirulent in a murine inhalation model. At the chromatin level, SPT7 deletion disrupted SAGA-dependent histone post-translational modifications, increasing H2B ubiquitination while reducing H3K14ac and H3K18ac levels. Proteomic profiling revealed reduced abundance of ribosomal, mitochondrial, and translational proteins and upregulation of lipid metabolic and secretory pathway components. Collectively, our findings establish Spt7 as a central integrator of SAGA-mediated chromatin regulation, proteomic balance, and virulence in C. neoformans and highlight the SAGA core as a potential antifungal target. Full article

Mass spectrometry has become an indispensable tool for the identification and quantification of epigenetic modifications, offering both high sensitivity and structural specificity. The two major classes of epigenetic modifications identified—DNA methylation and histone post-translational modifications—play fundamental roles in cancer development, underscoring the relevance of their precise quantification for understanding tumorigenesis and potential therapeutic targeting. In this scoping review, we included 89 studies that met the inclusion criteria for detailed methodological assessment. Among these, we compared pre-treatment workflows, analytical platforms, and acquisition modes employed to characterize epigenetic modifications in human samples and model systems. Our synthesis highlights the predominance of bottom-up strategies combined with Orbitrap-based platforms and data-dependent acquisition for histone post-translational modifications, whereas triple quadrupole mass spectrometers were predominant for DNA methylation quantification. We critically evaluate current limitations, including heterogeneity in validation reporting, insufficient coverage of combinatorial post-translational modifications, and variability in derivatization efficiency. Full article

Egg quality is a critical economic trait in poultry production, influencing consumer preference and production efficiency. The genetic and epigenetic regulation of egg quality involves complex biological pathways across various traits such as shell quality, albumen composition, and yolk biochemistry. This review synthesizes recent advances in the genetic, molecular, and epigenetic mechanisms that determine poultry egg quality. Specifically, it focuses on external traits such as eggshell strength, color, and thickness, and internal traits including albumen height, yolk composition, and the Haugh unit. Through genome-wide association studies (GWAS), quantitative trait loci (QTL) mapping, whole-genome sequencing (WGS), and multi-omics approaches, key candidate genes such as OC-116, CALB1, CA2 (shell formation), OVAL, SPINK5, SERPINB14 (albumen quality), and FGF9, PIAS1, NOX5 (lipid metabolism) have been identified. These genes play a pivotal role in shell biomineralization, albumen protein regulation, and yolk lipid transport. This review also explores the heritability of these traits, emphasizing the challenges posed by polygenic architecture and the influence of environmental factors. Furthermore, it addresses the dynamic spatiotemporal regulation of egg quality traits, including epigenetic layers such as DNA methylation, histone modifications, RNA methylation, and post-translational protein modifications. This paper highlights the application of these findings to breeding programs via genomic selection, marker-assisted breeding, and epigenetic engineering approaches. Future directions for precision breeding and the development of functional eggs with enhanced quality are also discussed. Full article

The peptidylarginine deiminase (PAD) family includes five isozymes (PAD1–4 and PAD6) with unique tissue distributions and substrate specificities. These enzymes facilitate citrullination, a post-translational modification where positively charged arginine residues are converted into neutral citrulline residues in the presence of calcium ions. This process significantly changes protein properties, affecting molecular interactions, structural stability, and biological functions. Over the past six years (2019–2025), there has been significant progress in understanding PAD activity mechanisms and their therapeutic potential. Recent discoveries include the regulated nuclear translocation of PAD2, PAD4’s specific role in forming cancer extracellular chromatin networks (CECNs), and the development of next-generation inhibitors with greatly improved pharmacological profiles. PAD4 is crucial in forming neutrophil extracellular traps (NETs). Citrullination of histones H3 and H4 by PAD4 destabilizes chromatin, helping release DNA-protein networks as an antibacterial defense. However, excessive NET formation can contribute to autoimmune diseases and thrombosis. Similarly, the bacterial peptidylarginine deiminase from Porphyromonas gingivalis (PPAD)—the only known prokaryotic citrullinating enzyme—plays a key role. Working with R-gingipains, PPAD triggers pathological citrullination of host proteins, leading to immune tolerance breakdown and linking periodontal disease with systemic autoimmune disorders such as rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease. Once thought to be a rare post-translational modification, citrullination is now understood as a vital regulatory mechanism in both normal physiology and disease, involving both internal processes of homeostasis and external mechanisms of bacterial pathogenesis. Full article

Background: Among primary malignant brain tumors in adults, glioblastoma is the most common and the most aggressive, characterized by profound metabolic reprogramming. This metabolic shift is essential for sustaining relentless proliferation and adapting to the challenging tumor microenvironment (TME). Central to this adaptation in glioma is the Warburg effect, which leads to excessive lactate production and accumulation, even in the presence of oxygen. This metabolic divergence significantly impacts the tumor immune microenvironment, promoting the recruitment of immunosuppressive cells and weakening the anti-tumor immune response. Core Content: This review provides a comprehensive analysis of the multifaceted roles of lactate in IDHwt glioma pathogenesis. It explores how lactate serves as a critical nexus connecting aberrant metabolism, epigenetic reprogramming (notably via histone lactylation), and immune evasion. The review delves into the molecular mechanisms by which lactate, particularly through the post-translational modification known as lactylation, directly modulates the epigenetic landscape to promote oncogene expression. Furthermore, it examines lactate’s role in acidifying the TME, promoting the immunosuppressive M2 polarization of glioma-associated macrophages (GAMs), and inhibiting the cytotoxic activity of T lymphocytes. Conclusions: This “lactate-centric” framework provides a unifying model that links metabolic dysregulation directly to malignant progression and therapeutic resistance (e.g., to TMZ). By elucidating this metabolic–epigenetic–immune axis, the review highlights a critical dependency that fuels glioma aggression. Finally, it discusses emerging therapeutic strategies aimed at targeting lactate production (LDHAi), transport (MCTi), and downstream epigenetic signaling (HDACi/p300i), offering novel avenues for integrative immunometabolic therapy. Full article

Chronic kidney disease is a significant global health burden and a leading cause of cardiovascular morbidity and mortality. Diabetes mellitus is the primary cause of kidney disease, driving the progression of both micro- and macrovascular complications. Sustained hyperglycemia initiates a cascade of deleterious molecular and cellular events, including mitochondrial dysfunction, inflammation, oxidative stress, and dysregulated apoptosis and autophagy, which collectively contribute to the progression of renal injury. Beyond these well-established mechanisms, a compelling body of evidence highlights the pivotal role of epigenetic alterations (such as DNA methylation, histone post-translational modifications, and non-coding RNAs) in mediated long-term kidney damage. The interplay between transcriptional and epigenetic regulation underlies the phenomenon of the “metabolic memory”, wherein cellular dysfunction persists even after glycemic control is achieved. This review synthesizes the current knowledge on mechanisms sustaining metabolic and epigenetic memory, with a particular focus on the epigenetic machinery that establishes and maintains these signals, a concept increasingly termed “epigenetic memory.” Given their reversible nature, epigenetic determinants are emerging as promising biomarkers and a compelling therapeutic avenue. Targeting these “epifactors” offers a novel strategy to halt progression to end-stage renal disease, thereby paving the way for precision medicine approaches in diabetes-related renal disease. Full article

Human cytomegalovirus (HCMV) is a herpesvirus (family) belonging to the beta herpesvirus subfamily that causes significant morbidity both in immunocompromised hosts (horizontal transmission) and during vertical transmission from mother to child. HCMV has the ability to establish a permanent latent infection with its host (even for decades), in which the DNA remains as a silent nuclear episome (latent phase) until reactivation after the appropriate conditions have occurred (lytic phase). The transition between the two phases (latent/lytic) is largely determined by the type of infected cell and the health status of the host, which ultimately corresponds to the epigenetic state of the infected cells. Lytic infection of the virus normally occurs in epithelial cells, endothelial cells, fibroblasts or macrophages, whereas the latent phase occurs when undifferentiated cells of the myeloid lineage, such as CD34+ hematopoietic progenitor cells, are infected. Epigenetic regulation of the viral genome begins with the formation of chromatin in the viral DNA just 30 min after infection and then evolves towards the latent or lytic phase. DNA viruses, including members of the herpesvirus family, are currently the subject of intense study regarding the role that epigenetics plays in controlling the viral life cycle, focusing primarily on the role of post-translational modifications (PTMs) of histones, as well as DNA methylation. Within the viral genome, nucleosomes are organized for the spatial/temporal expression of appropriate genes due to epigenetic modifications. Therefore, during the infection cycle, DNA chromatinization and chromatin modifications influence the expression of genes in the HCMV genome. This process is mediated by (i) enzymes called “writers”, which catalyze PTMs by adding chemical groups to proteins (acetylation, methylation, etc.); (ii) recruitment of specific transcription factors called “readers”, that bind to modified amino acid residues of proteins and act as interpreters of the PTM code; and (iii) “erasers”, enzymes that remove these modifications (e.g., HDACs). Indeed, recent advances in understanding the chromatin-based mechanisms of viral infections offer some promising strategies for therapeutic intervention that could be particularly useful in immunosuppressed recipients of transplants to avoid allograft rejection and infection by other opportunistic pathogens. In this review, we comprehensively examine the epigenetic regulation of the HCMV genome across distinct phases of viral infection, with particular attention to recent studies that significantly enriched the current knowledge about molecular mechanisms and future therapeutic perspectives. Full article

Post-translational modifications (PTMs) on protein lysine residues, including lactylation, methylation, acetylation, ubiquitination, and succinylation, serve as critical regulators in tumorigenesis and progression. Histone PTMs participate in tumor development by modulating chromatin structure and regulating gene expression. Notably, accumulating evidence reveals that PTMs target extensive non-histone substrates. These modifications occurring on non-histone proteins also contribute to tumor-associated biological processes. In this review, we systematically summarize the impact of non-histone PTMs on tumor and the tumor immune microenvironment (TIME). Additionally, we discuss crosstalk between distinct PTMs, which complicates the regulatory mechanisms of protein function. An in-depth research on PTMs in tumors holds new insights for exploring promising clinical therapeutic strategies. Full article

Lysine methylation is a regulatory post-translational modification with diverse roles across both histone and non-histone proteins. Despite its biological relevance, comprehensive characterization of lysine methylation remains analytically challenging due to its low stoichiometry, subtle mass changes, and the absence of standardized, robust enrichment strategies. Mass spectrometry (MS) has become the cornerstone of methylation analysis, supporting both targeted and proteome-wide investigations. In this review, we examine the evolution of MS-based workflows for lysine methylation, including advances in ionization and fragmentation techniques, high-resolution mass analyzers, and acquisition strategies such as data-independent acquisition (DIA) and parallel accumulation–serial fragmentation (PASEF). We evaluate bottom-up, middle-down, and top-down proteomic approaches and discuss enrichment methods ranging from immunoaffinity and chromatography to chemical derivatization. Particular attention is given to persistent challenges, including proteolytic constraints and isobaric interference, that complicate confident site-level resolution. Finally, we highlight emerging solutions and future directions aimed at improving the sensitivity, specificity, and reproducibility of lysine methylation profiling. Together, this synthesis provides a forward-looking roadmap for optimizing MS workflows in methyllysine proteomics. Full article

Omics approaches have advanced insight into molecular mechanisms of human obesity. We reviewed transcriptomic studies published between January 2020 and June 2025 that used human tissues or human cell lines and applied high-throughput RNA methods. Across these works three convergent themes emerged: (1) immune–inflammatory activation—particularly interferon-stimulated and innate immune signatures—linked to insulin resistance and visceral adiposity; (2) dysregulation of lipid and energy-metabolism pathways, including reduced lipolysis and β-oxidation in adipose tissue and liver; and (3) epigenetic and post-transcriptional regulation mediated by DNA methylation, histone modification, long noncoding RNAs, microRNAs and circular RNAs. Multi-omics integration (transcriptome with proteome, metabolome and microbiome) improved mechanistic interpretation and biomarker discovery but was limited by cohort heterogeneity and technical variation. We conclude that standardized, integrative multi-omics analyses in well-characterized, longitudinal human cohorts are required to translate molecular signatures into robust biomarkers and personalized therapeutic strategies for obesity. Full article

DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson’s Disease, Alzheimer’s Diseases, Multiple Sclerosis, and Huntington’s Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival. Full article

Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer. Full article

Herpes simplex virus (HSV) has a complicated life cycle including stages of primary lytic infection, latent infection, and reactivation. Although the HSV genomic DNA within the viral capsid is devoid of histones, it rapidly associates with histones upon entering the nucleus to form viral chromatin. This chromatin is not integrated into the host chromosome and displays features distinct from the cellular chromatin. The composition, structure, and post-translational modifications of the HSV chromatin change over the course of infection due to the actions of numerous viral and host molecules. In turn, the chromatin states influence the transcription profiles of viral genes at all stages of the viral life cycle and may dictate the outcomes of the lytic-latent balance. These mechanisms may be exploited to develop new antiviral therapeutics. This review summarizes current knowledge about the formation, regulation, and functions of the HSV chromatin and discusses the questions remaining to be answered. Full article

Lysine methylation is a critical post-translational modification catalyzed by lysine methyltransferases (KMTs), originally characterized in the regulation of histones. However, the breadth of non-histone targets remains largely unexplored. Here, we used a systematic peptide array-based approach to define a substrate preference motif for the SET-domain-containing KMT MLL4 (KMT2D), a member of the COMPASS complex and a known H3K4 methyltransferase. Using this motif, we identified CXXC finger protein 1 (CFP1), a core component of Setd1A/B complexes, as a putative MLL4 substrate. In vitro methyltransferase assays confirmed robust methylation of CFP1 by an MLL4-WRAD complex. Surprisingly, while initial predictions implicated K328, array-based methylation profiling revealed multiple lysine residues within CFP1’s lysine-rich basic domain as methylation targets, including K331, K335, K339, and K340. We further demonstrated that CFP1 methylation likely modulates its interaction with MLL4’s PHD cassettes and facilitates binding to Setd1A. Binding preferences of MLL4’s PHD1–3 and PHD4–6 domains varied with methylation state and site, suggesting non-histone methyl mark recognition by these cassettes. Pulldown assays confirmed that methylated, but not unmethylated, CFP1 binds Setd1A, supporting a potential methyl-switch mechanism. Together, our findings propose CFP1 as a potential non-histone substrate of MLL4 and suggest that MLL4 may regulate Setd1A/B function indirectly via CFP1 methylation. This study expands the substrate landscape of MLL4 and lays the groundwork for future investigations into non-histone methylation signaling in chromatin regulation. Full article

Specific expression of genes is fundamental for defining the identity and the functional state of cells. Sequence-specific transcription factors interpret the information contained in DNA sequence motifs and recruit cofactors to modify chromatin and control RNA polymerases. This multi-step process typically involves several transcription factors and cofactors with different enzymatic activities. Post-translational modifications (PTMs) of histones are one key mechanism to control chromatin structure and polymerase activity and thus gene transcription. The methylation of histone H3 at lysine 4 (H3K4) is a modification of accessible chromatin, including enhancers and promoters, and also sites of recombination and some forms of DNA damage. H3K4 methylation is catalyzed by six lysine methyltransferase complexes, referred to as KMT2 or COMPASS-like complexes. These are important in processes related to transcription and contribute to recombination in T and B cells. PRDM9 and ASH1L are H3K4 methyltransferases involved in meiotic recombination and DNA repair, respectively. In transcription, H3K4 mono- and tri-methylation are located at enhancers and promoters, respectively. These modifications, either alone or in combination with other histone PTMs, provide binding sites for transcriptional cofactors. Through these sites, H3K4 methylation affects chromatin accessibility and histone PTMs, typically resulting in a favorable environment for transcription. H3K4 tri-methylation also recruits and regulates RNA polymerase II (RNAPII) complexes, which interact with KMT2 complexes, generating positive feedforward loops to promote transcription. Thus, H3K4 methylation has broad activities that are key to different chromatin-associated processes. Full article