Search Results (33)

The human genome produces a large repertoire of non-coding RNAs (ncRNAs) with important regulatory roles in development, physiology, and most of diseases. Among these, long non-coding RNAs (lncRNAs) have emerged as key modulators of gene expression, chromatin organization, and cellular homeostasis, despite displaying remarkably low primary-sequence conservation across species. This apparent evolutionary paradox questions the limitations of predicting biological function based on conservation, particularly across different biological domains. Here, we examine current evidence on lncRNA evolution, with a focus on their roles in metabolic regulation compared with neurobiological processes. We hypothesize that lncRNAs involved in ancient and conserved pathways such as metabolism may be under stronger evolutionary constraint than those associated with higher-order, species-specific traits, although available data support a more nuanced interpretation. Functional importance often correlates poorly with linear sequence conservation and instead appears to depend on higher-level features, including RNA secondary or tertiary structure, genomic context, regulatory architecture, and interactions with conserved molecular partners. We propose a systematic comparative framework to empirically assess conservation among metabolism- and neuro-associated lncRNAs using phylogenetic, syntenic, structural, and expression-based metrics. Finally, we discuss the therapeutic implications of lncRNA biology, highlighting how a deeper understanding of their evolutionary and mechanistic properties may inform the development of more precise and effective RNA-targeting strategies. Together, these insights underscore the non-coding transcriptome as a critical frontier for both fundamental biology and precision medicine. Full article

Life evolved under a persistent 1 g field that is continuous, ubiquitous, and directionally structured. Here, we synthesize evidence across evolutionary biology, mechanobiology, and genome architecture to propose gravity as a mechanical boundary condition that helped canalize the emergence of complex multicellularity. Order-of-magnitude considerations indicate that gravity-derived hydrostatic loads can fall within force/pressure regimes relevant to nuclear and chromatin mechanosensitivity when transmitted through adhesion–cytoskeleton–LINC–lamina coupling. Comparative genomic and imaging frameworks suggest that complex animals increasingly rely on volumetric genome organization (packing domains and higher-order 3D architectures) that supports durable transcriptional memory and stable differentiated cell identities. Integrating these concepts with altered-gravity experiments, we argue that microgravity and hypergravity perturb chromatin topology and region-level transcription in rapid, largely reversible patterns consistent with a mechanically defined 1 g reference state. We advance a boundary-condition thesis: gravity is not a sole driver but a stable reference that likely contributed to the evolvability and long-term robustness of mechanogenomic architectures required for high-dimensional differentiation and tissue homeostasis. Full article

Sex chromosome imbalance is a genetic challenge in species with unequal X-chromosome numbers. Organisms have developed distinct strategies to control this imbalance through a process called dosage compensation. These strategies include X-chromosome inactivation in mammals mediated by the XIST long noncoding RNA and proteins recruited by XIST, and X-linked hypertranscription in male Drosophila driven by the Male-Specific Lethal (MSL) complex. In Caenorhabditis elegans, gene expression is downregulated from each of the two X chromosomes of hermaphrodites by half, thereby matching the levels in XO males. This is mediated by a specialized condensin-containing protein complex, the Dosage Compensation Complex (DCC). In all cases, the chromatin states on the sex chromosomes must be first established and then maintained for the entire lifetime of the organism. Although mammals and nematodes both use repression to achieve dosage compensation, the mechanisms are very different. Here, we summarize recent advances on how repressive chromatin states are established and maintained, with a focus on contrasting C. elegans dosage compensation to XIST-mediated X-chromosome inactivation. We review how specialized chromosome topology, repressive chromatin modifications, and higher-order nuclear architecture are established and maintained to achieve sex-specific regulation of the X chromosomes and highlight key outstanding questions and future research directions. Full article

The important economic traits of ruminants result from interactions between genetic background and environmental factors, but key traits such as reproductive performance, feed efficiency, disease resistance, and livestock product quality are often not fully explained by DNA sequence variations alone. Increasing evidence suggests that epigenetic regulation serves as a crucial molecular bridge connecting environmental stimuli with changes in gene expression, allowing organisms to exhibit stable and plastic phenotypic differences without altering the DNA sequence. This review provides a structured synthesis of recent research in the field of epigenetics in ruminants, elucidating how multiple layers of epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and higher-order chromatin structures, coordinate to regulate growth, development, reproductive performance, metabolic and immune homeostasis, and livestock product traits across different tissues and developmental stages. These epigenetic marks not only demonstrate high responsiveness to nutrition, management, and environmental stressors, but can exhibit context-dependent stability within the same tissue and physiological stage when environmental conditions are comparable, thereby contributing to the regulation of phenotypic plasticity and offering potential value as predictive biomarkers. Furthermore, epigenetic information can supplement our understanding of phenotypic variation in ways that traditional genomic selection methods are unable to capture, offering new data dimensions for the prediction and improvement of low heritability, environmentally sensitive traits. Overall, integrating epigenetic information with genomic selection strategies may improve the accuracy of ruminant trait prediction and enhance environmental adaptability. This integration also offers a conceptual basis and technical pathway for developing more precise and sustainable breeding systems. Full article

The Mediator complex is a central regulator of eukaryotic transcription, functioning as a dynamic molecular interface between gene-specific transcription factors and RNA polymerase II (Pol II). Although its overall architecture and general role in transcription have been extensively reviewed, accumulating genetic, genomic, and clinical evidence indicates that individual Mediator subunits make distinct and non-redundant contributions to human physiology and disease. In this review, we move beyond a generic description of Mediator function and present a subunit-resolved synthesis of Mediator biology with an emphasis on disease pathogenesis. A key feature of this review is a comprehensive table integrating disease associations and molecular functions of individual human Mediator subunits, enabling rapid assessment of functional specialization across the complex. We further discuss chromatin-based mechanisms of Mediator action, including cooperation with cohesin and architectural factors to regulate enhancer-promoter communication and higher-order genome organization. By organizing recent structural, mechanistic, and pathological findings into a unified framework, this review highlights how disruption of specific Mediator subunits contributes to cancer, developmental disorders, and metabolic disease, and outlines emerging opportunities for therapeutic intervention. Full article

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function. Full article

Background: G-quadruplexes (G4s) are non-canonical higher-order nucleic acid structures that form at guanine-rich motifs, with features spanning both secondary and tertiary structural levels. These dynamic structures play pivotal roles in diverse cellular processes. Endogenous G4s (eG4s) function through their dynamically formed structures, prompting the hypothesis that their thermostability, as a key structural property, may critically influence their functionality. This study investigates the relationship between G4 stability and other functional genomic signals within eG4 regions and examines its broader impact on chromatin organization and transcriptional regulation. Methods: We developed a mapping strategy to associate in vitro-derived thermostability metrics and multi-omics functional signals with eG4 regions. A stability-centric analytical framework combining correlation analysis and causal inference using the Bayesian networks was applied to decipher causal relationships between G4 stability and the other related signals. We further analyzed the association between the stability of transcription start site (TSS)-proximal eG4s and the biological functions of their downstream genes. Results: Our analyses demonstrate that G4 thermostability exerts causal effects on epigenetic states and transcription factor binding, thereby influencing chromatin and transcription regulation. We further show distinct network architectures for G4-binding versus non-binding transcription factors. Additionally, we find that TSS-proximal eG4s are enriched in genes involved in core proliferation and stress-response pathways, suggesting that eG4s may serve as regulatory elements facilitating rapid stress responses through genome-wide coordination. Conclusions: These findings establish thermostability—though measured in vitro—as an intrinsic property that shapes eG4 functionality. Our study not only provides novel insights into the functional relevance of G4 thermostability but also introduces a generalizable framework for high-throughput G4 data interpretation, significantly advancing the functional decoding of eG4s across biological contexts. Full article

Dynamic criticality—the balance between order and chaos—is fundamental to genome regulation and cellular transitions. In this study, we investigate the distinct behaviors of gene expression dynamics in MCF-7 breast cancer cells under two stimuli: heregulin (HRG), which promotes cell fate transitions, and epidermal growth factor (EGF), which binds to the same receptor but fails to induce cell-fate changes. We model the system as an open, nonequilibrium thermodynamic system and introduce a convergence-based approach for the robust estimation of information-thermodynamic metrics. Our analysis reveals that the Shannon entropy of the critical point (CP) dynamically synchronizes with the entropy of the rest of the whole expression system (WES), reflecting coordinated transitions between ordered and disordered phases. This phase synchronization is driven by net mutual information scaling with CP entropy dynamics, demonstrating how the CP governs genome-wide coherence. Furthermore, higher-order mutual information emerges as a defining feature of the nonlinear gene expression network, capturing collective effects beyond simple pairwise interactions. By achieving thermodynamic phase synchronization, the CP orchestrates the entire expression system. Under HRG stimulation, the CP becomes active, functioning as a Maxwell’s demon with dynamic, rewritable chromatin memory to guide a critical transition in cell fate. In contrast, under EGF stimulation, the CP remains inactive in this strategic role, passively facilitating a non-critical transition. These findings establish a biophysical framework for cell fate determination, paving the way for innovative approaches in cancer research and stem cell therapy. Full article

Background: Cellular senescence in response to ionizing radiation (IR) limits the replication of damaged cells by causing permanent cell cycle arrest. However, IR can induce pro-survival signaling pathways that reduce the extent of radiation-induced cytotoxicity and promote the development of radioresistance. The differential incorporation of histone variant H2A.J has profound effects on higher-order chromatin organization and on establishing the epigenetic state of radiation-induced senescence. However, the precise epigenetic mechanism and function of H2A.J overexpression in response to IR exposure still needs to be elucidated. Methods: Primary (no target, NT) and genetically modified fibroblasts overexpressing H2A.J (H2A.J-OE) were exposed to 20 Gy and analyzed 2 weeks post-IR for radiation-induced senescence by immunohistochemistry and immunofluorescence microscopy. Transcriptome signatures were analyzed in (non-)irradiated NT and H2A.J-OE fibroblasts by RNA sequencing. Since H2A.J plays an important role in the epidermal homeostasis of human skin, the oncogenic potential of H2A.J was investigated in cutaneous squamous cell carcinoma (cSCC). The tissue microarrays of cSCC were analyzed for H2A.J protein expression pattern by automated image analysis. Results: In response to radiation-induced DNA damage, the overexpression of H2A.J impairs the formation of senescence-associated heterochromatin foci (SAHF), thereby inhibiting the SAHF-mediated silencing of proliferation-promoting genes. The dysregulated activation of cyclins and cyclin-dependent kinases disturbs cell cycle arrest in irradiated H2A.J-OE fibroblasts, thereby overcoming radiation-induced senescence. Comparative transcriptome analysis revealed significantly increased WNT16 signaling in H2A.J OE fibroblasts after IR exposure, promoting the fundamental mechanisms of tumor development and progression, including the activation of the epithelial–mesenchymal transition. The quantitative analysis of cSCCs revealed that undifferentiated tumors are associated with high nuclear H2A.J expression, related with greater oncogenic potential. Conclusion: H2A.J overexpression induces radioresistance and promotes oncogenic transformation through the activation of WNT16 signaling pathway functions. H2A.J-associated signatures may improve risk stratification by identifying patients with more aggressive cSCC who may require radiotherapy with increased doses. Full article

Histones, which make up nucleosomes, undergo various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation. In particular, histone methylation serves different cellular functions depending on the location of the amino acid residue undergoing modification, and is tightly regulated by the antagonistic action of histone methyltransferases and demethylases. The SUV39H family of histone methyltransferases (HMTases) are evolutionarily conserved from fission yeast to humans and play an important role in the formation of higher-order chromatin structures called heterochromatin. The SUV39H family HMTases catalyzes the methylation of histone H3 lysine 9 (H3K9), and this modification serves as a binding site for heterochromatin protein 1 (HP1) to form a higher-order chromatin structure. While the regulatory mechanism of this family of enzymes has been extensively studied in various model organisms, Clr4, a fission yeast homologue, has made an important contribution. In this review, we focus on the regulatory mechanisms of the SUV39H family of proteins, in particular, the molecular mechanisms revealed by the studies of the fission yeast Clr4, and discuss their generality in comparison to other HMTases. Full article

Purpose: Radiation-induced senescence is characterized by profound changes in chromatin organization with the formation of Senescence-Associated-Heterochromatin-Foci (SAHF) and DNA-Segments-with-Chromatin-Alterations-Reinforcing-Senescence (DNA-SCARS). Importantly, senescent cells also secrete complex combinations of pro-inflammatory factors, referred as Senescence-Associated-Secretory-Phenotype (SASP). Here, we analyzed the epigenetic mechanism of histone variant H2A.J in establishing radiation-induced senescence. Experimental Design: Primary and genetically-modified lung fibroblasts with down- or up-regulated H2A.J expression were exposed to ionizing radiation and were analyzed for the formation of SAHF and DNA-SCARS by immunofluorescence microscopy. Dynamic changes in chromatin organization and accessibility, transcription factor recruitment, and transcriptome signatures were mapped by ATAC-seq and RNA-seq analysis. The secretion of SASP factors and potential bystander effects were analyzed by ELISA and RT-PCR. Lung tissue of mice exposed to different doses were analyzed by the digital image analysis of H2A.J-immunohistochemistry. Results: Differential incorporation of H2A.J has profound effects on higher-order chromatin organization and on establishing the epigenetic state of senescence. Integrative analyses of ATAC-seq and RNA-seq datasets indicate that H2A.J-associated changes in chromatin accessibility of regulatory regions decisively modulates transcription factor recruitment and inflammatory gene expression, resulting in an altered SASP secretome. In lung parenchyma, pneumocytes show dose-dependent H2A.J expression in response to radiation-induced DNA damage, therefore contributing to pro-inflammatory tissue reactions. Conclusions: The fine-tuned incorporation of H2A.J defines the epigenetic landscape for driving the senescence programme in response to radiation-induced DNA damage. Deregulated H2A.J deposition affects chromatin remodeling, transcription factor recruitment, and the pro-inflammatory secretome. Our findings provide new mechanistic insights into DNA-damage triggered epigenetic mechanisms governing the biological processes of radiation-induced injury. Full article

Transcriptional regulation is pivotal for all living organisms and is required for adequate response to environmental fluctuations and intercellular signaling molecules. For precise regulation of transcription, cells have evolved regulatory systems on the genome architecture, including the chromosome higher-order structure (e.g., chromatin loops), location of transcription factor (TF)-binding sequences, non-coding RNA (ncRNA) transcription, chromatin configuration (e.g., nucleosome positioning and histone modifications), and the topological state of the DNA double helix. To understand how these genome-chromatin architectures and their regulators establish tight and specific responses at the transcription stage, the fission yeast fbp1 gene has been analyzed as a model system for decades. The fission yeast fbp1 gene is tightly repressed in the presence of glucose, and this gene is induced by over three orders of magnitude upon glucose starvation with a cascade of multi-layered regulations on various levels of genome and chromatin architecture. In this review article, we summarize the multi-layered transcriptional regulatory systems revealed by the analysis of the fission yeast fbp1 gene as a model system. Full article

The 3D genome organization and its dynamic modulate genome function, playing a pivotal role in cell differentiation and development. CTCF and cohesin, acting as the core architectural components involved in chromatin looping and genome folding, can also recruit other protein or RNA partners to fine-tune genome structure during development. Moreover, systematic screening for partners of CTCF has been performed through high-throughput approaches. In particular, several novel protein and RNA partners, such as BHLHE40, WIZ, MAZ, Aire, MyoD, YY1, ZNF143, and Jpx, have been identified, and these partners are mostly implicated in transcriptional regulation and chromatin remodeling, offering a unique opportunity for dissecting their roles in higher-order chromatin organization by collaborating with CTCF and cohesin. Here, we review the latest advancements with an emphasis on features of CTCF partners and also discuss the specific functions of CTCF-associated complexes in chromatin structure modulation, which may extend our understanding of the functions of higher-order chromatin architecture in developmental processes. Full article

Chromatin compaction and regulation are essential processes for the normal function of all organisms, yet knowledge on how archaeal chromosomes are packed into higher-order structures inside the cell remains elusive. In this study, we investigated the role of archaeal architectural proteins Alba and Cren7 in chromatin folding and dynamics. Atomic force microscopy revealed that Sulfolobus solfataricus chromatin is composed of 28 nm fibers and 60 nm globular structures. In vitro reconstitution showed that Alba can mediate the formation of folded DNA structures in a concentration-dependent manner. Notably, it was demonstrated that Alba on its own can form higher-order structures with DNA. Meanwhile, Cren7 was observed to affect the formation of Alba-mediated higher-order chromatin structures. Overall, the results suggest an interplay between Alba and Cren7 in regulating chromatin compaction in archaea. Full article