Search Results (395)

Plants must continuously balance the trade-offs between growth and defense, a constraint that is exacerbated by biotic and abiotic stresses, particularly when they occur together. Ethylene (ET) serves as a central, integrative regulatory node controlling this by linking developmental programs to stress-responsive signaling networks. Advances at the molecular and systems levels have revealed that ET mediates the redistribution of metabolic resources via coordinated regulation of its synthesis, perception, and downstream signaling. The ETR (Ethylene Receptor)-CTR1 (Constitutive Triple Response 1)-EIN2 (Ethylene Insensitive 2)-EIN3(Ethylene Insensitive 3) signaling module lies at the core of this network, integrating multiple hormonal pathways. Through dynamic crosstalk with jasmonic acid (JA), salicylic acid (SA), abscisic acid (ABA), auxin (AUX), and gibberellins (GA), ET enables the fine-tuned coordination of growth inhibition, immune activation, and stress acclimation in response to environmental fluctuations. Processes such as induced systemic resistance, programmed cell death, and architectural plasticity further reinforce this regulatory framework, with ethylene-responsive transcription factors, including ERFs (ethylene responsive factor gene family) and WRKYs, acting as critical convergence points. Emerging insights into ACC (1-aminocyclopropane-1-carboxylic acid)-dependent signaling, chromatin remodeling, and tissue-specific regulation expand the functional scope of ET beyond traditional hormone paradigms. At the same time, the ability of pathogens to manipulate ET signaling underscores its dual role in both promoting immunity and facilitating susceptibility. By integrating molecular, physiological, and ecological perspectives, this review highlights ET as a central coordinator of plant stress resilience and growth optimization, providing a unifying framework for understanding how plants adapt to complex and dynamic environments. Full article

In vertebrates, SWI/SNF complexes, also known as BRG1/BRM-associated factor (BAF) complexes, come in three major subtypes, canonical BAF (cBAF or BAF), polybromo-associated BAF (PBAF) and non-canonical BAF (ncBAF), that are targeted to different types of chromosomal cis-regulatory gene expression control elements. Approximately 20% of malignancies exhibit mutations in genes coding for subunits of the SWI/SNF family of ATP-dependent chromatin remodelling complexes. SMARCD is an essential evolutionarily conserved subunit of these complexes in all eukaryotes. Whilst the integral role of SMARCD in targeting and stabilising the SWI/SNF complexes is conserved from yeast to plants to humans, the three human SMARCD paralogs display specific expression patterns underlying their functional divergence. Although, all three SMARCD paralogs exhibit context-dependent roles in cancer, acting as both tumour suppressors and oncogenes, it is SMARCD1 that appears to show the broadest oncogenic footprint across malignancies, driving proliferation, invasion and metastasis in diverse cancer types. Here we review the recent literature pertaining to the molecular and cellular roles of the mammalian SMARCD paralogs and discuss their roles in oncogenesis from those perspectives. Full article

Ischemic stroke elicits a rapid and sustained innate immune response that critically contributes to blood–brain barrier (BBB) breakdown and secondary neuronal injury. Among the cellular mediators involved, neutrophil extracellular traps (NETs) have emerged as potent effectors of neurovascular damage. However, the regulatory mechanisms governing NET formation and their prolonged impact on BBB integrity remain incompletely understood. Increasing evidence indicates that NET formation is an epigenetically regulated process, requiring chromatin remodeling, histone modifications, DNA methylation changes and non-coding RNA-mediated control within neutrophils under ischemic conditions. These epigenetic events license the extrusion of DNA–histone–enzyme complexes that directly injure endothelial cells, degrade tight junction proteins, activate innate immune signaling pathways and amplify neuroinflammatory cascades at the neurovascular unit. Moreover, NET-derived chromatin and associated mediators can induce transcriptional and epigenetic alterations in BBB cells, thereby sustaining barrier permeability and impairing vascular repair mechanisms. In this review, we synthesize current knowledge on the epigenetic regulation of NET formation and delineate how epigenetically regulated NETs function as key disruptors of BBB integrity in ischemic stroke. Understanding this NETosis–epigenetics–BBB axis may uncover novel therapeutic strategies aimed at preserving neurovascular integrity and limiting post-stroke brain injury. Full article

Background and Clinical Significance: SWI/SNF chromatin remodeling complex-deficient malignancies constitute an aggressive group of undifferentiated tumors defined by inactivation of core subunits including SMARCA4 (BRG1) or SMARCB1 (INI1). In the head and neck, these tumors predominate in the sinonasal tract; oral cavity presentations are exceedingly rare, with reported cases predominantly representing metastatic disease. Peri-implant gingival masses in clinical practice are overwhelmingly reactive, but their occasional malignant nature mandates timely biopsy and thorough pathologic workup. We report the first comprehensively molecularly characterized case of a peri-implant gingival SWI/SNF complex-deficient tumor with confirmed biallelic SMARCA4 inactivation. Case Presentation: A 75-year-old man presented with a one-week history of a rapidly enlarging exophytic erythematous peri-implant gingival mass in the right posterior mandible (region 44–47). Incisional biopsy demonstrated an undifferentiated high-grade tumor with epithelioid, plasmablastoid, and focally rhabdoid morphology with necrosis. Immunohistochemistry showed complete loss of BRG1 (SMARCA4) with retained INI1 (SMARCB1), EMA positivity, Ki-67 of approximately 100%, and negativity across all lineage-specific markers (hematolymphoid, epithelial, melanocytic, endothelial, squamous). Comprehensive next-generation sequencing (Oncomine Comprehensive Assay Plus) confirmed biallelic SMARCA4 inactivation via a truncating nonsense mutation (p.Trp1346Ter; VAF 73.85%) combined with copy number loss, establishing the molecular mechanism underlying BRG1 protein loss. Co-occurring alterations included homozygous CDKN2A/CDKN2B deletion, MTAP loss (9p21.3), clonal TP53 and KEAP1 mutations, and intermediate–high tumor mutational burden (13.3 mutations/Mb) with microsatellite stability. The patient initiated carboplatin–paclitaxel and achieved a partial response at one month with further shrinkage by four months. This case illustrates a rare oral cavity manifestation of SWI/SNF complex deficiency arising in a peri-implant location, with a diagnostic workup that required integration of immunohistochemistry and molecular profiling for definitive characterization. The MTAP deletion co-occurring with homozygous CDKN2A/B loss identifies a potentially actionable synthetic lethal vulnerability to MAT2A and PRMT5 inhibitors currently under clinical investigation. An occult primary site could not be fully excluded due to absence of a dedicated staging workup. Conclusions: Rapidly enlarging peri-implant gingival masses should prompt timely biopsy and SWI/SNF marker testing when histology is high-grade and lineage-ambiguous. NGS-based molecular profiling confirms diagnosis, elucidates mechanism, and reveals actionable targets in this rare tumor class. Full article

Heart failure (HF) is a complex and heterogeneous clinical syndrome defined by progressive structural, functional, and molecular alterations in the myocardium, representing a significant global health challenge. Beyond haemodynamic compromise, HF arises from intricate interactions among neurohormonal activation, chronic inflammation, oxidative stress, mitochondrial dysfunction, impaired calcium handling, and extracellular matrix remodelling. These processes drive maladaptive cardiac remodelling and progressive functional decline across multiple HF phenotypes, including HF with reduced (HFrEF), mildly reduced (HFmrEF), and preserved ejection fraction (HFpEF). Recent advances in molecular biology have highlighted the critical roles of genomic, epigenetic, and transcriptomic mechanisms in the progression of HF. DNA methylation, histone modifications, chromatin remodelling, and non-coding RNAs regulate gene expression in response to environmental and metabolic stimuli, thereby connecting systemic risk factors to cardiac dysfunction. Proteomic and post-translational modifications, such as phosphorylation, acetylation, and redox signalling, modulate protein function and contribute to contractile impairment and metabolic dysregulation. Metabolomic studies have revealed significant changes in myocardial energy metabolism, including reduced oxidative capacity, decreased metabolic flexibility, and limited bioenergetic reserves. The integration of multi-omics approaches—including genomics, transcriptomics, proteomics, metabolomics, and epigenomics—has provided unprecedented insight into the biological heterogeneity of HF, facilitating the identification of distinct molecular subtypes and novel therapeutic targets. Systems biology and network-based analyses, supported by artificial intelligence and machine learning, enable the synthesis of complex datasets and enhance risk classification, prognosis, and personalised treatment approaches. This narrative review synthesises the current understanding of the molecular mechanisms underlying HF, with particular emphasis on the interplay between metabolic and epigenetic regulation in disease progression. It also highlights emerging translational opportunities, including omics-based biomarkers, targeted therapies, and precision medicine approaches. Despite significant advances, challenges remain in translating these findings into clinical practice, underscoring the need for standardised methodologies, extensive validation, and integrative frameworks. Ultimately, a systems-level, multi-omics perspective is crucial for redefining HF as a biologically stratified condition in the landscape of advancing tailored cardiovascular medicine. Full article

Economic traits in livestock and poultry arise from the intricate interplay between genetic inheritance and environmental factors, mediated largely by epigenetic regulation. Histone modifications, particularly methylation and acetylation, serve as fundamental epigenetic mechanisms that dynamically remodel chromatin architecture and regulate gene expression in response to developmental and environmental cues. By bridging the gap between static DNA sequences and complex phenotypes, these dynamic marks offer a novel perspective for elucidating trait formation. This review examines the regulatory roles of histone modifications in shaping key economic traits, focusing on skeletal muscle development, fat deposition, and reproductive performance. Furthermore, we highlight two prospective strategies for integrating histone modification data into modern breeding programs: utilizing comprehensive epigenomic maps as novel biomarkers for precision selection, and implementing targeted nutritional regimens to program early phenotypic development. Despite substantial mechanistic advances, critical challenges persist, including high detection costs, inherent tissue specificity, and the necessity to validate transgenerational stability. Looking forward, the integration of multi-omics approaches is anticipated to propel animal breeding beyond traditional genomic selection toward an era of precise epigenomic design. Full article

The ubiquitously transcribed tetratricopeptide repeat Y-linked gene (UTY/KDM6C), a catalytically impaired histone demethylase encoded on the Y chromosome, has garnered increasing attention for its emerging roles in tumorigenesis and cancer progression. Despite high sequence homology with its X-linked paralog UTX/KDM6A, UTY exhibits markedly reduced or absent H3K27me3 demethylase activity due to critical amino acid substitutions in its Jumonji C domain. Consequently, UTY primarily functions through non-enzymatic mechanisms, acting as a scaffold in chromatin-remodelling complexes like COMPASS and SWI/SNF, or mediating protein–protein interactions that regulate transcriptional programs independent of demethylation. This aligns with epigenetic dysregulation in cancers, where imbalances in repressive H3K27me3 and active H3K4me either drive tumour suppressor silencing or oncogene activation. Unlike frequently mutated UTX in cancers such as breast, renal cell carcinoma, and acute myeloid leukaemia, UTY’s contributions in cancer are less defined, constrained by male-specific expression. Emerging evidence suggests UTY as a context-dependent tumour suppressor in AML and squamous-like pancreatic ductal adenocarcinoma. While direct functional validation remains limited in several cancer types, UTY is increasingly implicated as a potential tumour suppressor in haematological malignancies and prostate cancer. Therapeutically targeting UTY’s scaffold functions shows promise for male-specific cancers and merits future investigation. Full article

Ubiquitin-specific protease 7 (USP7/HAUSP) is one of the most studied deubiquitinating enzymes and plays a crucial role in regulating numerous cellular processes, making it a promising therapeutic target. In the nucleus, USP7 partially colocalizes with PML nuclear bodies (PML-NB)—multifunctional membraneless organelles involved in post-translational modifications and protein complexes assembly. The molecular basis and functional significance of this association remain uncharacterized. In this study, comparison of USP7 and PML interactomes revealed a significant overlap of 166 shared proteins. Functional enrichment analysis showed that USP7 and PML may operate within a common molecular context related to transcriptional regulation, chromatin remodeling, and DNA damage responses. Furthermore, these processes are also linked to cellular senescence and human aging (CellAge and GenAge databases). Focused analysis of overlaps between the USP7 interactome and core PML-NB proteins identified 61 proteins forming a dense “small-world” network. Most are prone to liquid–liquid phase separation, are intrinsically disordered, and serve as substrates for SUMOylation or ubiquitination. These findings not only expand our understanding of the molecular functions of USP7 but also highlight PML-NB as an important cellular context for investigating mechanisms associated with USP7 activity. Full article

Background: Adipogenesis is governed by a complex interplay between transcriptional regulation and epigenetic remodeling. While many transcriptional pathways have been well characterized, less is known about how chromatin-level regulation shapes the timing of gene expression, particularly in large animal models such as pigs. In this study, we investigated histone modification patterns associated with four key adipogenic transcription factor genes—PPARG, GATA2, CEBPA, and CEBPB—in porcine mesenchymal stem cells (MSCs) undergoing adipogenic differentiation. Methods: Using RT-qPCR and ChIP-qPCR, we profiled gene transcription levels and epigenetic marks, including promoter- and exon-specific enrichment of the activating histone marks H3K9ac and H4K8ac, as well as the repressive mark H4K20me3, across six time points (day 0, 2, 4, 6, 8, and 10). Results: Although PPARG and GATA2 are located in close proximity on porcine chromosome 13, they exhibited distinct histone modification profiles. PPARG showed progressive promoter acetylation (H4K8ac) accompanied by transcriptional activation, whereas GATA2 displayed decreased exon acetylation (H3K9ac) associated with declining expression. In contrast, the H4K20me3 profile was similar for both genes, suggesting no direct association with their transcriptional activity. Interestingly, CEBPA (chromosome 6) and CEBPB (chromosome 17) exhibited temporally distinct histone modification patterns consistent with their roles in intermediate and early stages of adipogenic differentiation, respectively. Increased enrichment of the H3K9ac mark preceded the rise in transcript levels of the analyzed genes. Promoter regions showed higher enrichment of H4K8ac compared with exonic regions. A higher level of H4K20me3 was also observed for CEBPA and CEBPB than for PPARG and GATA2, which appeared to be more related to chromosomal localization than to direct transcriptional regulation. Conclusions: Together, these results reveal complex interactions between transcriptional dynamics and selected histone modifications that depend on both the gene analyzed and the stage of adipocyte differentiation. This study provides new insights into the epigenetic regulation of porcine adipogenesis and highlights chromatin context as an additional layer influencing transcriptional control. Full article

Background/Objectives: Loss of heterozygosity (LOH) in meningioma has been known for more than two decades. It has been shown that LOH on chromosome 1p36 is an independent marker of meningioma recurrence and progression. ARID1A, a tumor suppressor gene located on chromosome 1p36.11, is part of the chromatin-regulating SWI/SNF complex whose subunits are altered in 20% of cases across all tumor entities. Methods: Using our newly developed indirect enzyme-linked immunosorbent assay (ELISA), we investigated whether tumors with or without LOH 1p differ in ARID1A expression in 61 meningiomas. To study possible links between ARID1A and ARID1B, we tested for LOH 6q in association with LOH 1p using a PCR-based microsatellite approach. ARID1B, another member of the SWI/SNF complex, is located on 6q25.3. Additionally, we compared our ELISA results with immunohistochemistry data staining of ARID1A in tissue sections known to harbor LOH 1p. Results: Our results indicate that meningiomas harboring LOH 1p have significantly lower ARID1A levels compared to tumors without LOH 1p. In free nuclear protein fractions, reductions were up to 32% (CI: 6–58.7%). Interestingly, we found that ARID1A levels were significantly lower in tumors with recurrence and/or multiple localizations. In addition, our analysis of chromosome 6q uncovered a significantly strong correlation between LOH 1p and LOH 6q (p < 0.0001). Conclusions: These results highlight the importance of ARID1A in meningioma malignization and indicate for the first time functional evidence for LOH 1p. Full article

Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and contributes to a wide spectrum of human disorders, including developmental syndromes, premature aging, and multiple cancers. Here, we review how chromatin state and remodeling complexes shape detection, signaling, and resolution of DNA double-strand breaks, and we examine how their misregulation drives disease and presents opportunities for therapeutic intervention. Specifically, we discuss how post-translational modifications and ATP-dependent chromatin remodeling complexes contribute to DNA damage repair with a particular focus on DNA double-strand breaks, one of the most deleterious DNA lesions. We summarize how chromatin remodeling and histone post-translational modifications regulate DNA repair pathway choice, and how these processes are essential for safeguarding genomic integrity and preventing human disease. Finally, we discuss emerging concepts and major unanswered questions in the context of chromatin function and DNA double-strand break repair, with a focus on exploring the emerging literature on the role of chromatin compartments and topological associated domains for orchestrating DNA repair within chromatin and safeguarding genomic stability. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition that occurs in early childhood, characterized by a broad range of clinical manifestations and impairments in social communication. It represents one of the most prevalent neurodevelopmental disorders, affecting approximately 1% of the general population. The phenotypic heterogeneity of ASD arises from different genetic causes, including chromosomal abnormalities, copy number variants (CNVs), and single-nucleotide variants (SNVs), which may occur as de novo or inherited events. Moreover, the polygenic and multifactorial nature of ASD, together with epigenetic regulation and environmental influences, contributes substantially to its complex genetic architecture. Molecular diagnosis remains challenging and relies on multiple genomic approaches, such as array comparative genomic hybridization (array-CGH), whole-exome sequencing (WES), and whole-genome sequencing (WGS); however, the diagnostic yields of these methods remain limited, reflecting the complexity of ASD’s genetic architecture. Notably, ASD-associated genes converge on key biological pathways, particularly those involved in transcriptional regulation, chromatin remodeling, synaptic function, and neuronal signaling. These include well-established risk genes such as CHD8, ADNP, ARID1B, SHANK3, SYNGAP1, SCN2A, GRIN2B, FOXP1, and DYRK1A, among others. This review summarizes the current knowledge on the genetic basis of ASD, highlighting key aspects of its complex genetic architecture. By integrating evidence from major clinical and research databases, it provides a clearer understanding of the underlying mechanisms, supporting improved diagnosis and future research and therapeutic strategies. Full article

Nuclear lamins are the core molecular bridge linking the extracellular mechanical microenvironment to intranuclear gene regulation, and play a central regulatory role in cellular mechanosensation and mechanotransduction. Here, we systematically integrate the latest global research progress on nuclear lamins, delineating the cascade regulatory mechanism by which lamins mediate the transmission of mechanical signals across the nuclear envelope and the subsequent regulation of chromatin remodeling and epigenetic modification, with a focus on the molecular characteristics and functional specificity of distinct nuclear lamin subtypes and their interaction modes with the Linker of Nucleoskeleton and Cytoskeleton complex (LINC complex) and chromatin. Existing studies have established that nuclear lamins are mainly divided into three categories: A-type lamins (Lamin A/C), B-type lamins (Lamin B1, B2), and germ cell-specific subtypes. Among these, A-type lamins directly determine the mechanical stiffness of the nucleus and serve as the core mediators of intranuclear mechanical signal transduction. Each subtype of B-type nuclear lamins has a well-defined, non-redundant functional division: Lamin B1 and Lamin B2 indirectly maintain nuclear structural stability and regulate epigenetic status by anchoring facultative heterochromatin and constitutive heterochromatin, respectively. Notably, Lamin A/C distributed in the nucleoplasm also bears significant mechanical tension, which challenges the long-standing view that the mechanical functions of nuclear lamins are restricted to the nuclear envelope region. After mechanical force is transmitted across the nuclear envelope to nuclear lamins via the LINC complex, it can regulate the spatial conformation of chromatin and epigenetic modifications, thereby determining core cellular life activities including proliferation, differentiation, and migration. Dysregulation of this pathway is closely associated with a wide spectrum of human diseases, including cardiovascular diseases, progeria, muscular dystrophy, and neurodevelopmental disorders. Taken together, this review systematically delineates the hierarchical regulatory network of the “LINC complex–nuclear lamina–chromatin” axis, advances our understanding of the fundamental principles of cellular mechanobiology, and provides a theoretical framework for deciphering the pathological mechanisms and developing targeted therapeutic drugs for related diseases. Full article

Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the p75NTR occupy a central position at the intersection between neuronal differentiation programs and malignant plasticity. While high TrkA and TrkC expression is associated with adrenergic identity, differentiation competence, and favourable clinical outcome, TrkB, frequently sustained by BDNF-driven autocrine loops, characterises mesenchymal-like, therapy-resistant states enriched in metabolic and inflammatory adaptations. Importantly, in NB, the dysregulation of neurotrophin signalling rarely arises from recurrent genetic alterations of neurotrophic tyrosine receptor kinase (NTRK) loci. Instead, Trk receptor expression is dynamically shaped by promoter methylation, polycomb repressive complex 2/Enhancer of Zeste homolog 2 (PRC2/EZH2)-dependent chromatin repression, MYCN-driven transcriptional silencing, enhancer rewiring, and microRNA-mediated control. These epigenetic mechanisms govern reversible transitions along the adrenergic–mesenchymal (ADRN–MES) continuum, enabling tumour cells to adapt to microenvironmental and therapeutic stress. Single-cell and spatial multi-omics approaches have further revealed that Trk-associated phenotypes are embedded within complex regulatory circuits integrating receptor tyrosine kinase (RTK) networks, cytokine signalling, metabolic remodelling, and stromal reinforcement. Here, we provide a comprehensive synthesis of the epigenetic and microenvironmental mechanisms regulating neurotrophin receptors in NB, with particular emphasis on how chromatin plasticity and cell-state transitions reshape Trk-dependent signalling outputs. We discuss advanced three-dimensional and organoid-based models that recapitulate niche-specific regulation of the Trk axis and evaluate emerging therapeutic strategies combining epigenetic modulators, differentiation-inducing agents, and RTK-targeted compounds. Understanding the temporal and spatial dynamics of Trk signalling may open new opportunities to therapeutically stabilise differentiation states and disrupt adaptive resistance programs in high-risk NB. Full article

NANOG overexpression has been reported to reverse aging-associated decline in mesenchymal stem/stromal cell (MSC) function, but the molecular machinery engaged by NANOG in MSCs remains incompletely defined. Here, we applied APEX proximity labeling coupled with quantitative mass spectrometry to define the NANOG proximity interactome (proxeome) in human MSCs. Of 1040 quantified proteins, 828 were significantly enriched in the APEX-NANOG (H₂O₂ labeling) samples, consistent with a broad NANOG-centered neighborhood rather than a single stoichiometric complex. Enriched proteins encompass RNA-processing pathways (including splicing/RNP factors and selected m6A-related proteins), transcriptional coactivation and elongation control (Mediator and 7SK/P-TEFb regulators), chromatin repression/poising modules (Polycomb and HDAC/NuRD/CoREST/SIN3), ATP-dependent chromatin remodeling (BAF/SWI-SNF), three-dimensional genome organization and replication-coupled chromatin maintenance (CTCF/cohesin, CHAF1A, RIF1, UHRF1), and regulators of MSC identity and signal integration (Hippo/mechanotransduction and TGFβ-linked transcriptional circuits). Together, these data provide a spatial proteomic map of NANOG-associated nuclear neighborhoods in MSCs and a foundation for mechanistic hypotheses for how NANOG may stabilize stem-like programs. Full article