Nucleus (Austin, Tex.)最新文献

The vascular network, uniquely sensitive to mechanical changes, translates biophysical forces into biochemical signals for vessel function. This process relies on the cell's architectural integrity, enabling uniform responses to physical stimuli. Recently, the nuclear envelope (NE) has emerged as a key regulator of vascular cell function. Studies implicate nucleoskeletal elements (e.g. nuclear lamina) and the linker of nucleoskeleton and cytoskeleton (LINC) complex in force transmission, emphasizing nucleo-cytoskeletal communication in mechanotransduction. The nuclear pore complex (NPC) and its component proteins (i.e. nucleoporins) also play roles in cardiovascular disease (CVD) progression. We herein summarize evidence on the roles of nuclear lamina proteins, LINC complex members, and nucleoporins in endothelial and vascular cell mechanotransduction. Numerous studies attribute NE components in cytoskeletal-related cellular behaviors to insinuate dysregulation of nucleocytoskeletal feedback and nucleocytoplasmic transport as a mechanism of endothelial and vascular dysfunction, and hence implications for aging and vascular pathophysiology.

The nuclear envelope plays an indispensable role in the spatiotemporal organization of chromatin and transcriptional regulation during the intricate process of cell differentiation. This review outlines the distinct regulatory networks between nuclear envelope proteins, transcription factors and epigenetic modifications in controlling the expression of cell lineage-specific genes during differentiation. Nuclear lamina with its associated nuclear envelope proteins organize heterochromatin via Lamina-Associated Domains (LADs), proximal to the nuclear periphery. Since nuclear lamina is mechanosensitive, we critically examine the impact of extracellular forces on differentiation outcomes. The nuclear envelope is spanned by nuclear pore complexes which, in addition to their central role in transport, are associated with chromatin organization. Furthermore, mutations in the nuclear envelope proteins disrupt differentiation, resulting in developmental disorders. Investigating the underlying nuclear envelope controlled regulatory mechanisms of chromatin remodelling during lineage commitment will accelerate our fundamental understanding of developmental biology and regenerative medicine.

Chromatin is a dynamic polymer in constant motion. These motions are heterogeneous between cells and within individual cell nuclei and are profoundly altered in response to DNA damage. The shifts in chromatin motions following genomic insults depend on the temporal and physical scales considered. They are also distinct in damaged and undamaged regions. In this review, we emphasize the role of chromatin tethering and loop formation in chromatin dynamics, with the view that pulsing loops are key contributors to chromatin motions. Chromatin tethers likely mediate micron-scale chromatin coherence predicted by polymer models and measured experimentally, and we propose that remodeling of the tethers in response to DNA breaks enables uncoupling of damaged and undamaged chromatin regions.

Over the past 25 years, nuclear envelope (NE) perturbations have been reported in various experimental models with mutations in the LMNA gene. Although the hypothesis that NE perturbations from LMNA mutations are a fundamental feature of striated muscle damage has garnered wide acceptance, the molecular sequalae provoked by the NE damage and how they underlie disease pathogenesis such as cardiomyopathy (LMNA cardiomyopathy) remain poorly understood. We recently shed light on one such consequence, by employing a cardiomyocyte-specific Lmna deletion in vivo in the adult heart. We observed extensive NE perturbations prior to cardiac function deterioration with collateral damage in the perinuclear space. The Golgi is particularly affected, leading to cytoprotective stress responses that are likely disrupted by the progressive deterioration of the Golgi itself. In this review, we discuss the etiology of LMNA cardiomyopathy with perinuclear 'organelle trauma' as the nexus between NE damage and disease pathogenesis.

Adar-mediated adenosine-to-inosine (A-to-I) RNA editing mainly occurs in nucleus and diversifies the transcriptome in a flexible manner. It has been a challenging task to identify beneficial editing sites from the sea of total editing events. The functional Ser>Gly auto-recoding site in insect Adar gene has uneditable Ser codons in ancestral nodes, indicating the selective advantage to having an editable status. Here, we extended this case study to more metazoan species, and also looked for all Drosophila recoding events with potential uneditable synonymous codons. Interestingly, in D. melanogaster, the abundant nonsynonymous editing is enriched in the codons that have uneditable counterparts, but the Adar Ser>Gly case suggests that the editable orthologous codons in other species are not necessarily edited. The use of editable versus ancestral uneditable codon is a smart way to infer the selective advantage of RNA editing, and priority might be given to these editing sites for functional studies due to the feasibility to construct an uneditable allele. Our study proposes an idea to narrow down the candidates of beneficial recoding sites. Meanwhile, we stress that the matched transcriptomes are needed to verify the conservation of editing events during evolution.

The nucleus not only is a repository for DNA but also a center of cellular and nuclear mechanotransduction. From nuclear deformation to the interplay between mechanosensing components and genetic control, the nucleus is poised at the nexus of mechanical forces and cellular function. Understanding the stresses acting on the nucleus, its mechanical properties, and their effects on gene expression is therefore crucial to appreciate its mechanosensitive function. In this review, we examine many elements of nuclear mechanotransduction, and discuss the repercussions on the health of cells and states of illness. By describing the processes that underlie nuclear mechanosensation and analyzing its effects on gene regulation, the review endeavors to open new avenues for studying nuclear mechanics in physiology and diseases.

Most of the genome is transcribed into RNA but only 2% of the sequence codes for proteins. Non-coding RNA transcripts include a very large number of long noncoding RNAs (lncRNAs). A growing number of identified lncRNAs operate in cellular stress responses, for example in response to hypoxia, genotoxic stress, and oxidative stress. Additionally, lncRNA plays important roles in epigenetic mechanisms operating at chromatin and in maintaining chromatin architecture. Here, we address three lncRNA topics that have had significant recent advances. The first is an emerging role for many lncRNAs in cellular stress responses. The second is the development of high throughput screening assays to develop causal relationships between lncRNAs across the genome with cellular functions. Finally, we turn to recent advances in understanding the role of lncRNAs in regulating chromatin architecture and epigenetics, advances that build on some of the earliest work linking RNA to chromatin architecture.

Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from the assembly of scaffolding PML proteins and various partners. Recent crystal structure analyses revealed essential self-interacting domains, while liquid-liquid phase separation contributes to their formation. PML bodies orchestrate post-translational modifications, particularly stress-induced SUMOylation, impacting target protein functions. Serving as hubs in multiple signaling pathways, they influence cellular processes like senescence. Dysregulation of PML expression contributes to diseases, including cancer, highlighting their significance. Therapeutically, PML bodies are promising targets, exemplified by successful acute promyelocytic leukemia treatment with arsenic trioxide and retinoic acid restoring PML bodies. Understanding their functions illuminates both normal and pathological cellular physiology, guiding potential therapies. This review explores recent advancements in PML body biogenesis, biochemical activity, and their evolving biological roles.

Accumulating evidence suggests that the nuclear envelope (NE) is not just a target, but also a mediator of apoptosis. We showed recently that the NE protein nesprin-2 has pro-apoptotic activity, which involves its subcellular redistribution and Bcl-2 proteins. Here we further characterize the pro-apoptotic activity of nesprin-2 focusing on its redistribution. We assessed the redistribution kinetics of endogenous nesprin-2 tagged with GFP relative to apoptosis-associated mitochondrial dysfunction. The results show apoptosis-induced GFP-nesprin-2G redistribution occurred by two different modes - complete and partial, both lead to appearance of nesprin-2G near the mitochondria. Moreover, GFP-nesprin-2 redistribution is associated with reduction in mitochondrial membrane potential and mitochondrial outer membrane permeabilization and precedes the appearance of morphological features of apoptosis. Our results show that nesprin-2G redistribution and translocation near mitochondria is an early apoptotic effect associated with mitochondrial dysfunction, which may be responsible for the pro-apoptotic function of nesprin-2.