Search Results (218)

Calcium/calmodulin-dependent protein kinase II (CaMKII) comprises multiple isoforms with distinct nuclear variants that exert transcriptional control in a context-dependent manner. Among them, CaMKIIδB and δ9 in the heart, and CaMKIIγ in the nervous system, have emerged as regulators of chromatin dynamics, transcription factor activity, and developmental gene programs. Nuclear localization is driven by splice-dependent nuclear localization sequences, with phosphorylation at defined serine residues modulating import and retention. Evidence supports CaMKII-dependent phosphorylation of class IIa HDACs (Ser467/Ser632 in HDAC4), linking CaMKII to MEF2 activation in cardiac hypertrophy, and interactions with NF-κB and HSF1 further expand its nuclear repertoire. In the nervous system, CaMKIIγ contributes to kinase-dependent gene expression, potentially influencing plasticity and disease susceptibility. While these mechanisms highlight nuclear CaMKII as an isoform-specific regulator of transcription, direct evidence remains elusive, and several CaMKII putative substrates require further validation. This review synthesizes current knowledge on nuclear CaMKII isoforms, emphasizes established mechanistic pathways, and outlines unsolved questions critical for understanding their roles in development, disease progression, and therapeutic targeting. Full article

Glucosinolates (GSLs) are nitrogen- and sulfur-containing secondary metabolites central to the defense, development, and environmental responsiveness of Brassicaceae species. While the enzymatic steps and transcriptional networks underlying GSL biosynthesis have been extensively characterized, mounting evidence reveals that chromatin-based processes add a critical, yet underexplored, layer of regulatory complexity. Recent studies highlight the roles of DNA methylation, histone modifications, and non-coding RNAs in modulating the spatial and temporal expression of GSL biosynthetic genes and their transcriptional regulators in response to developmental cues and environmental signals. This review provides a comprehensive overview of GSL classification, biosynthetic pathway architecture, transcriptional regulation, and metabolite transport, with a focus on emerging epigenetic mechanisms that shape pathway plasticity. We also discuss how these insights may be leveraged in precision breeding and epigenome engineering, including the use of CRISPR/dCas9-based chromatin editing and epigenomic selection, to optimize GSL content, composition, and stress resilience in cruciferous crops. Integrating transcriptional and epigenetic regulation thus offers a novel framework for the dynamic control of specialized metabolism in plants. Full article

Background/Objectives: β-Carotene oxygenase-2 (BCO2) is a mitochondrial carotenoid-cleaving enzyme expressed in multiple tissues, including the lungs. While BCO2 regulates carotenoid handling, its role in shaping pulmonary immune architecture and antiviral responses is unknown. We hypothesized that BCO2 deficiency reprograms epithelial–innate circuits and alters antiviral outcomes. Methods: BCO2-knockout (KO) and C57BL/6J wild-type (WT) mice underwent lung single-cell RNA sequencing (scRNA-seq), immunoblotting, and intranasal SARS-CoV-2 challenge to assess cell-type heterogeneity, pathway programs (by gene set variation analysis, GSVA), and antiviral responses. Results: scRNA-seq resolved 14 major lung cell populations with cell-type-specific pathway shifts. Compared with WT, BCO2 KO lungs showed increased conventional dendritic cells and natural killer (NK) cells, with reductions in macrophages, B cells, and endothelial cells. In KO alveolar type II cells, GSVA indicated a stress-adapted metabolic program. Ciliated epithelium exhibited vitamin-K-responsive and axoneme-remodeling signatures with attenuated glucocorticoid and very-low-density lipoprotein remodeling. Innate lymphoid type 2 cells favored fatty acid oxidation and chromatin dynamics with reduced mitochondrial activity. NK cells were biased toward constitutive chemokine/cytokine secretion and counter-inflammatory signaling. Immunoblotting confirmed the elevated level of interferon regulatory factor-3 protein in BCO2-KO lungs. Functionally, BCO2-KO mice had improved outcomes after intranasal SARS-CoV-2 exposure. Conclusions: Loss of BCO2 reconfigures the pulmonary immune landscape and enhances antiviral responsiveness in mice. These findings identify BCO2 as a nutrient-linked enzyme with immunomodulatory impact and highlight cell-state changes as candidate mechanisms for improved antiviral tolerance. Full article

ATPase family AAA domain-containing protein 2 (ATAD2) has been recognized as a key oncogene that regulates chromatin remodeling, transcription, and cancer progression. As a member of the bromodomain (BRD) family, ATAD2 plays a crucial role in epigenetic modifications and is associated with multiple malignancies. Despite being considered an undruggable target in the past, crystallography and computational modeling have significantly accelerated ATAD2 drug discovery and development. This review provides a comprehensive overview of the structural features, functional roles, and biological significance of ATAD2, particularly in the context of cancer. We present an in-depth overview of different molecular strategies reported in the literature to suppress ATAD2 expression, including genetic and pharmacological approaches, and discuss their mechanistic and therapeutic implications. Particular emphasis is given to recent efforts in developing small-molecule inhibitors, detailing their binding interactions, therapeutic potential, and challenges in clinical translation. In addition, we performed alanine scanning calculations on molecular dynamics (MD)-simulated trajectories derived from protein–ligand complexes based on X-ray co-crystal structures containing three distinct ligands with different binding modes. This analysis provided critical insights into the binding interface of BRD-ATAD2, enhancing our understanding of its ligand interactions. Furthermore, we examine the emerging roles of ATAD2 in mediating resistance to cancer therapies, underscoring its potential as a target for overcoming drug resistance. By integrating structural insights, mechanistic studies, drug discovery efforts, and the challenges of developing ATAD2-targeted cancer therapies, this review emphasizes the need for further research to optimize ATAD2 inhibition strategies and explore its full therapeutic potential in oncology. Full article

RBL1 (p107) is a member of the retinoblastoma (RB) family of pocket proteins involved in cell cycle regulation and E2F transcriptional repression. While its promoter contains conserved E2F motifs, the integrated regulation of RBL1 by upstream tumor suppressor pathways remains incompletely understood. Here, we investigate the p53-dependent transcriptional regulation of RBL1 and dissect the contribution of its tandem E2F binding sites to this mechanism. Luciferase assays in synchronized cells demonstrated that these two conserved E2F sites are required for cell cycle-dependent activation of the RBL1 promoter. Overexpression of p53 showed that p53 represses RBL1 promoter activity in an E2F site-dependent manner. Using HCT116 p21 knockout cells, we revealed that this p53-dependent repression is mediated by p21. Chromatin immunoprecipitation confirmed dynamic in vivo binding of E2F1–3 and E2F4, while DNA pull-down assays revealed specific in vitro recruitment of RB, p107, and E2F1-4 to the two E2F sites, along with weak binding of MuvB components. Additional experiments in RB^–/– and LIN37^–/– knockouts showed that RB/E2F repressing complex plays the main role in repressing the RBL1 promoter, while E2F4, p107, and p130 can support this effect to a lesser extent. Overall, our findings demonstrate that p53 controls RBL1 expression indirectly through the p21–RB–E2F pathway by utilizing two E2F binding sites within the RBL1 promoter. Full article

Pubertal molting represents a pivotal transition in the life cycle of crustaceans, marking the shift from somatic growth to reproductive development. In mud crabs, mating is known to facilitate this process, yet the molecular mechanisms remain poorly understood. Here, we applied full-length transcriptome sequencing to characterize changes in gene expression and alternative splicing (AS) across post-mating ovarian development. AS analysis revealed extensive transcript diversity, predominantly alternative first exon (AF) and alternative 5′ splice site (A5) events, enriched in genes linked to chromatin remodeling, protein regulation, and metabolism, underscoring AS as a fine-tuning mechanism in ovarian development. Comparative analyses revealed profound molecular reprogramming after mating. In the UM vs. M1 comparison, pathways related to serotonin and catecholamine signaling were enriched, suggesting early neuroendocrine regulation. Serotonin likely promoted, while dopamine inhibited, oocyte maturation, indicating a potential “inhibition–activation” switch. In the UM vs. M3 comparison, pathways associated with oxidative phosphorylation, ATP biosynthesis, and lipid metabolism were upregulated, reflecting heightened energy demands during vitellogenesis. ECM-receptor interaction, HIF-1, and IL-17 signaling pathways further pointed to structural remodeling and tissue regulation. Enhanced antioxidant defenses, including upregulation of SOD2, CAT, GPX4, and GSTO1, highlighted the importance of redox homeostasis. Together, these findings provide the first comprehensive view of transcriptional and splicing dynamics underlying post-mating ovarian maturation in Scylla paramamosain, offering novel insights into the molecular basis of crustacean reproduction. Full article

The methylation of CpG sites with 5mC mark is a dynamic epigenetic modification. However, the relationship between the methylation and the surrounding genomic sequence context remains poorly explored. Investigation of the allele methylation provides an opportunity to decipher the interplay between differences in the primary DNA sequence and epigenetic variation. Here, we performed high-coverage long-read whole-genome direct DNA sequencing of one individual using Oxford Nanopore technology. We also used Illumina whole-genome sequencing of the parental genomes in order to identify allele-specific methylation sites with a trio-binning approach. We have compared the results of the haplotype-specific methylation detection and revealed that trio binning outperformed other approaches that do not take into account parental information. Also, we analysed the cis-regulatory effects of the genomic variations for influence on CpG methylation. To this end, we have used available Deep Learning models trained on the primary DNA sequence to score the cis-regulatory potential of the genomic loci. We evaluated the functional role of the allele-specific epigenetic changes with respect to gene expression using long-read Nanopore RNA sequencing. Our analysis revealed that the frequency of SNVs near allele-specific methylation positions is approximately four times higher compared to the biallelic methylation positions. In addition, we identified that allele-specific methylation sites are more conserved and enriched at the chromatin states corresponding to bivalent promoters and enhancers. Together, these findings suggest that significant impact on methylation can be encoded in the DNA sequence context. In order to elucidate the effect of the SNVs around sites of allele-specific methylation, we applied the Deep Learning model for detection of the cis-regulatory modules and estimated the impact that a genomic variant brings with respect to changes to the regulatory activity of a DNA loci. We revealed higher cis-regulatory impact variants near differentially methylated sites that we further coupled with transcriptomic long-read sequencing results. Our investigation also highlights technical aspects of allele methylation analysis and the impact of sequencing coverage on the accuracy of genomic phasing. In particular, increasing coverage above 30X does not lead to a significant improvement in allele-specific methylation discovery, and only the addition of trio binning information significantly improves phasing. We investigated genomic variation in a single human individual and coupled computational discovery of cis-regulatory modules with allele-specific methylation (ASM) profiling. In this proof-of-concept analysis, we observed that SNPs located near methylated CpG sites on the same haplotype were enriched for sequence features suggestive of high-impact regulatory potential. This finding—derived from one deeply sequenced genome—illustrates how phased genetic and epigenetic data analyses can jointly put forward a hypotheses about the involvement of regulatory protein machinery in shaping allele-specific epigenetic states. Our investigation provides a methodological framework and candidate loci for future studies of genomic imprinting and cis-mediated epigenetic regulation in humans. Full article

Histone variant macroH2A1 (mH2A1) has been widely recognized as a suppressor of gene expression. Recently, a cell cycle-dependent deposition of mH2A1 was discovered in mouse cells, but whether this process exists in human chromatin is unclear, which might be crucial for related diseases, particularly cancer. In this study, with native chromatin immunoprecipitation (nChIP-seq), we firstly demonstrate that dynamic mH2A1 domains occur in both normal and cancerous human cells and have conserved enrichment patterns across species. Our findings further provide new epigenetic insights into the role of mH2A1 in malignant proliferation, offering a novel perspective for future cancer research. Full article

The rising global prevalence of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, is paralleled by an increased risk of colitis-associated colorectal cancer. Persistent intestinal inflammation promotes genetic instability and epigenetic reprogramming within epithelial and immune cells, driving the multistep transition from inflammation to neoplasia. This review integrates human and preclinical model evidence with literature mining and bioinformatic analyses of genetic, epigenetic, and ncRNA data to dissect molecular mechanisms driving colitis-associated colorectal cancer from chronic inflammation. We highlight how pro-inflammatory cytokines (e.g., TNF-α, IL-6), oxidative stress, and microbial dysbiosis converge on key transcriptional regulators such as NF-κB and STAT3, inducing DNA methylation and histone modifications (e.g., H3K27me3); altering chromatin dynamics, gene expression, and non-coding RNA networks (e.g., miR-21, MALAT1, CRNDE); ultimately reshaping pathways involved in proliferation, apoptosis, and immune evasion. This review updates new potential associations of entities with these diseases, in their networks of interaction, summarizing major aspects of genetic and chromatin-level regulatory mechanisms in inflammatory bowel disease and colorectal cancer, and emphasizing how these interactions drive the inflammatory-to-neoplastic transition. By underscoring the reversibility of epigenetic changes, we explore their translational potential in early detection, surveillance, and precision epigenetic therapy. Understanding the interplay between genetic mutations and chromatin remodeling provides a roadmap for improving diagnostics and personalized treatments in inflammatory bowel disease-associated colorectal carcinogenesis. Full article

The mammalian genome is hierarchically packaged into distinct functional units, including chromatin loops, topologically associating domains, compartments and chromosome territories. This structural organization is fundamentally important because it orchestrates essential nuclear functions that underpin normal cellular identity and organismal development. In this review, we synthesize current understanding of the intricate relationship between genome architecture and its critical biological roles. We discuss how hierarchical structures are dynamically established and maintained by architectural proteins, transcription factors, epigenetic regulators and non-coding RNAs via distinct mechanisms. Importantly, we focus on the functional consequences of three-dimensional (3D) genome organization and discuss how it modulates fundamental biological processes such as transcription, gene co-expression, epigenetic modification, DNA replication and repair. We also examine the dynamics of 3D genome organization during cellular differentiation, early embryonic development and organogenesis, followed by discussing how structural disruptions are mechanistically linked to various human diseases. Understanding the biological function of 3D genome organization is thus not only essential for deciphering fundamental nuclear processes but also holds significant promise for elucidating disease etiologies and developing effective therapeutics. Full article

Polycomb group (PcG) proteins are pivotal in maintaining gene silencing through epigenetic mechanisms, particularly by catalyzing Histone H3 lysine 27 trimethylation (H3K27me3) via the Polycomb Repressive Complex 2 (PRC2) complex. These modifications are crucial for regulating developmental pathways and environmental stress responses in plants. Despite their importance, the PcG gene family has not been systematically explored in rice (Oryza sativa). In this study, 15 OsPcG genes were identified in the Nipponbare genome, spanning 12 chromosomes and classified into distinct phylogenetic groups. Structural and conserved motif analyses revealed high sequence conservation, while collinearity and Ka/Ks analyses indicated gene family expansion through segmental duplication under purifying selection. Promoter element prediction suggested that many OsPcG genes are responsive to plant hormones and abiotic stress cues. Transcriptome analysis under salt treatment highlighted OsPcG5 as a key salt-responsive gene, with qRT-PCR confirming its dynamic expression. Subcellular localization showed OsPcG5 residing in both the nucleus and plasma membrane, suggesting multifunctional roles. Additionally, overexpression of OsFIE2—a PRC2 component—resulted in elevated H3K27me3 levels and abnormal plant height, linking it to chromatin modification and development. These findings contribute to our understanding of PcG gene functions in rice and offer potential genetic resources for enhancing salt tolerance through epigenetic approaches. Full article

Promyelocytic leukemia nuclear bodies (PML-NBs) are dynamic membrane-less organelles (MLOs) located in the nucleus that serve as regulatory hubs for multiple cellular processes. This review examines current understanding of PML-NB structure, assembly mechanisms, and their diverse functional roles. We discuss how PML-NBs interact with chromatin to influence gene expression, regulate transcription factors, and participate in protein quality control. The review highlights their critical functions in tumor suppression, particularly in acute promyelocytic leukemia, and their role in intrinsic antiviral defense against various pathogens. Despite significant advances in the field, key questions remain regarding the mechanistic triggers of PML-NB formation and their common roles across different pathologies. Further elucidation of these aspects may provide valuable insights for developing therapeutic approaches targeting the PML-NB axis in disease treatment. Full article

Asthma is a chronic inflammatory airway disease influenced by both genetic and environmental factors. Recent insights have underscored the pivotal role of epigenetic regulation in the pathogenesis and heterogeneity of asthma. This review focuses on key epigenetically important regulators categorized as writers, erasers, and readers that govern DNA methylation, histone modifications, and RNA modifications. These proteins modulate gene expression without altering the underlying DNA sequence, thereby influencing immune responses, airway remodeling, and disease severity. We highlight the structural and functional dynamics of histone acetyltransferases (e.g., p300/CBP), histone deacetylases (e.g., SIRT family), DNA methyltransferases (DNMT1, DNMT3A), demethylases (TET1), and methyl-CpG-binding proteins (MBD2) in shaping chromatin accessibility and transcriptional activity. Additionally, the m6A RNA modification machinery including METTL3, METTL14, FTO, YTHDF1/2, IGF2BP2, and WTAP is explored for its emerging significance in regulating post-transcriptional gene expression during asthma progression. Structural characterizations of these proteins reveal conserved catalytic domains and interaction motifs, mirroring their respective families such as SIRTs, p300/CBP, DNMT1/3A, and YTHDF1/2 critical to their epigenetic functions, offering mechanistic insight into their roles in airway inflammation and immune modulation. By elucidating these pathways, this review provides a framework for the development of epigenetic biomarkers and targeted therapies. Future directions emphasize phenotype-specific epigenomic profiling and structure-guided drug design to enable precision medicine approaches in asthma management. Full article

Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality worldwide. Increasing evidence indicates that epigenetic mechanisms, which are potentially reversible and modifiable by environmental and nutritional factors, play a key role in hepatocarcinogenesis. Histone deacetylases (HDACs) are fundamental epigenetic modulators that regulate chromatin dynamics and ultimately gene transcription with important pathophysiological implications and promising therapeutic perspectives. The role of HDACs is gaining interest for the understanding of HCC development mechanisms and for the potential therapeutic implications of their natural and synthetic inhibitors. This review provides an overview on HDACs classification and their peculiar expression patterns in HCC, with a focus on zinc-dependent histone deacetylases (HDACs). HDAC inhibitors (HDACis), both synthetic and natural-derived compounds, are also discussed for their emerging effects in optimizing the anticancer efficacy of the current therapeutic strategies. Novel dietary-derived and bioactive compounds-based interventions are discussed in the context of HCC management as promising nutri-epigenetic avenues. Targeting HDACs bears a significant therapeutic potential for HCC management while further confirmatory clinical investigation is warranted. Full article

Epigenetic regulation, particularly DNA methylation, plays a crucial role in plant adaptation to environmental stresses by modulating gene expression without altering the underlying DNA sequence. In response to major abiotic stresses such as salinity, drought, heat, cold, and heavy metal toxicity, plants undergo dynamic changes in DNA methylation patterns. These modifications are orchestrated by DNA methyltransferases and demethylases with variations depending on plant species, genetic background, and ontogenic phase. DNA methylation affects the expression of key genes involved in cellular, physiological, and metabolic processes essential for stress tolerance. Furthermore, it contributes to the establishment of stress memory, which can be transmitted across generations, thereby enhancing long-term plant resilience. The interaction of DNA methylation with other epigenetic mechanisms, including histone modifications, small RNAs, and chromatin remodeling, adds layers of regulatory complexity. Recent discoveries concerning N6-methyladenine have opened new avenues for understanding the epigenetic landscape in plant responses to abiotic stress. Overall, this review addresses the central role of DNA methylation in regulating plant stress responses and emphasizes its potential for application in crop improvement through epigenetic and advanced biotechnological approaches. Full article