Functional architecture in the cell nucleus

2001 ◽  
Vol 356 (2) ◽  
pp. 297-310 ◽  
Author(s):  
Miroslav DUNDR ◽  
Tom MISTELI
Keyword(s):  
Gene Expression ◽  
Cell Nucleus ◽  
Molecular Mechanisms ◽  
Dynamic Properties ◽  
Three Dimensional ◽  
Nuclear Architecture ◽  
Structural Framework ◽  
And Function ◽  
Biological Methods

The major functions of the cell nucleus, including transcription, pre-mRNA splicing and ribosome assembly, have been studied extensively by biochemical, genetic and molecular methods. An overwhelming amount of information about their molecular mechanisms is available. In stark contrast, very little is known about how these processes are integrated into the structural framework of the cell nucleus and how they are spatially and temporally co-ordinated within the three-dimensional confines of the nucleus. It is also largely unknown how nuclear architecture affects gene expression. In order to understand how genomes are organized, and how they function, the basic principles that govern nuclear architecture and function must be uncovered. Recent work combining molecular, biochemical and cell biological methods is beginning to shed light on how the nucleus functions and how genes are expressed in vivo. It has become clear that the nucleus contains distinct compartments and that many nuclear components are highly dynamic. Here we describe the major structural compartments of the cell nucleus and discuss their established and proposed functions. We summarize recent observations regarding the dynamic properties of chromatin, mRNA and nuclear proteins, and we consider the implications these findings have for the organization of nuclear processes and gene expression. Finally, we speculate that self-organization might play a substantial role in establishing and maintaining nuclear organization.

Cell biology of transcription and pre-mRNA splicing: nuclear architecture meets nuclear function

2000 ◽  
Vol 113 (11) ◽  
pp. 1841-1849 ◽  
Author(s):  
T. Misteli
Keyword(s):  
Gene Expression ◽  
Cell Nucleus ◽  
Cell Biology ◽  
Nuclear Architecture ◽  
Molecular Techniques ◽  
Mrna Splicing ◽  
Cellular Organization ◽  
Control Of Gene Expression ◽  
Expression Of Genes

Gene expression is a fundamental cellular process. The basic mechanisms involved in expression of genes have been characterized at the molecular level. A major challenge is now to uncover how transcription, RNA processing and RNA export are organized within the cell nucleus, how these processes are coordinated with each other and how nuclear architecture influences gene expression and regulation. A significant contribution has come from cell biological approaches, which combine molecular techniques with microscopy methods. These studies have revealed that the mammalian cell nucleus is a complex but highly organized organelle, which contains numerous subcompartments. I discuss here how two essential nuclear processes - transcription and pre-mRNA splicing - are spatially organized and coordinated in vivo, and how this organization might contribute to the control of gene expression. The dynamic nature of nuclear proteins and compartments indicates a high degree of plasticity in the cellular organization of nuclear functions. The cellular organization of transcription and splicing suggest that the morphology of nuclear compartments is largely determined by the activities of the nucleus.

scholarly journals Structure and function of outer dynein arm intermediate and light chain complex

2016 ◽  
Vol 27 (7) ◽  
pp. 1051-1059 ◽  
Author(s):  
Toshiyuki Oda ◽  
Tatsuki Abe ◽  
Haruaki Yanagisawa ◽  
Masahide Kikkawa
Keyword(s):  
Molecular Mechanisms ◽  
Electron Tomography ◽  
3D Structure ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Chain Complex ◽  
Flagellar Motility ◽  
Chemically Induced Dimerization ◽  
And Function

The outer dynein arm (ODA) is a molecular complex that drives the beating motion of cilia/flagella. Chlamydomonas ODA is composed of three heavy chains (HCs), two ICs, and 11 light chains (LCs). Although the three-dimensional (3D) structure of the whole ODA complex has been investigated, the 3D configurations of the ICs and LCs are largely unknown. Here we identified the 3D positions of the two ICs and three LCs using cryo–electron tomography and structural labeling. We found that these ICs and LCs were all localized at the root of the outer-inner dynein (OID) linker, designated the ODA-Beak complex. Of interest, the coiled-coil domain of IC2 extended from the ODA-Beak to the outer surface of ODA. Furthermore, we investigated the molecular mechanisms of how the OID linker transmits signals to the ODA-Beak, by manipulating the interaction within the OID linker using a chemically induced dimerization system. We showed that the cross-linking of the OID linker strongly suppresses flagellar motility in vivo. These results suggest that the ICs and LCs of the ODA form the ODA-Beak, which may be involved in mechanosignaling from the OID linker to the HCs.

scholarly journals LncRNA HOTAIR: A Potential Prognostic Factor and Therapeutic Target in Human Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoru Xin ◽  
Qianan Li ◽  
Jinyong Fang ◽  
Tiejun Zhao
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Regulatory Function ◽  
Human Cancers ◽  
Human Solid Tumors ◽  
And Function ◽  
The Impact ◽  
Lncrna Hotair

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of gene expression and physiological processes. LncRNAs are a class of ncRNAs of 200 nucleotides in length. HOX transcript antisense RNA (HOTAIR), a trans-acting lncRNA with regulatory function on transcription, can repress gene expression by recruiting chromatin modifiers. HOTAIR is an oncogenic lncRNA, and numerous studies have determined that HOTAIR is highly upregulated in a wide variety of human cancers. In this review, we briefly summarize the impact of lncRNA HOTAIR expression and functions on different human solid tumors, and emphasize the potential of HOTAIR on tumor prognosis and therapy. Here, we review the recent studies that highlight the prognostic potential of HOTAIR in drug resistance and survival, and the progress of therapies developed to target HOTAIR to date. Furthermore, targeting HOTAIR results in the suppression of HOTAIR expression or function. Thus, HOTAIR knockdown exhibits great therapeutic potential in various cancers, indicating that targeting lncRNA HOTAIR may serve as a promising strategy for cancer therapy. We also propose that preclinical studies involving HOTAIR are required to provide a better understanding of the exact molecular mechanisms underlying the dysregulation of its expression and function in different human cancers and to explore effective methods of targeting HOTAIR and engineering efficient and targeted drug delivery methods in vivo.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

scholarly journals Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
M. Asada-Utsugi ◽  
K. Uemura ◽  
M. Kubota ◽  
Y. Noda ◽  
Y. Tashiro ◽  
...  
Keyword(s):  
Memory Function ◽  
Three Dimensional ◽  
Excitatory Synapses ◽  
Missense Mutations ◽  
Glutamatergic Synapses ◽  
Learning Tasks ◽  
Transmission Electron ◽  
Nmdar Activation ◽  
And Function

AbstractN-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Serial analysis of gene expression (SAGE) during porcine embryo development

2004 ◽  
Vol 16 (2) ◽  
pp. 87 ◽  
Author(s):  
Le Ann Blomberg ◽  
Kurt A. Zuelke
Keyword(s):  
Gene Expression ◽  
Functional Genomics ◽  
Embryo Development ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Transgenic Animals ◽  
Specific Gene ◽  
Research Strategies

Functional genomics provides a powerful means for delving into the molecular mechanisms involved in pre-implantation development of porcine embryos. High rates of embryonic mortality (30%), following either natural mating or artificial insemination, emphasise the need to improve the efficiency of reproduction in the pig. The poor success rate of live offspring from in vitro-manipulated pig embryos also hampers efforts to generate transgenic animals for biotechnology applications. Previous analysis of differential gene expression has demonstrated stage-specific gene expression for in vivo-derived embryos and altered gene expression for in vitro-derived embryos. However, the methods used to date examine relatively few genes simultaneously and, thus, provide an incomplete glimpse of the physiological role of these genes during embryogenesis. The present review will focus on two aspects of applying functional genomics research strategies for analysing the expression of genes during elongation of pig embryos between gestational day (D) 11 and D12. First, we compare and contrast current methodologies that are being used for gene discovery and expression analysis during pig embryo development. Second, we establish a paradigm for applying serial analysis of gene expression as a functional genomics tool to obtain preliminary information essential for discovering the physiological mechanisms by which distinct embryonic phenotypes are derived.

scholarly journals Filopodyan: An open-source pipeline for the analysis of filopodia

2017 ◽  
Vol 216 (10) ◽  
pp. 3405-3422 ◽  
Author(s):  
Vasja Urbančič ◽  
Richard Butler ◽  
Benjamin Richier ◽  
Manuel Peter ◽  
Julia Mason ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dynamic Properties ◽  
Cell Types ◽  
Molecular Heterogeneity ◽  
Interactive Editing ◽  
Motile Cells ◽  
Different Cell Types ◽  
Neuronal Growth Cones

Filopodia have important sensory and mechanical roles in motile cells. The recruitment of actin regulators, such as ENA/VASP proteins, to sites of protrusion underlies diverse molecular mechanisms of filopodia formation and extension. We developed Filopodyan (filopodia dynamics analysis) in Fiji and R to measure fluorescence in filopodia and at their tips and bases concurrently with their morphological and dynamic properties. Filopodyan supports high-throughput phenotype characterization as well as detailed interactive editing of filopodia reconstructions through an intuitive graphical user interface. Our highly customizable pipeline is widely applicable, capable of detecting filopodia in four different cell types in vitro and in vivo. We use Filopodyan to quantify the recruitment of ENA and VASP preceding filopodia formation in neuronal growth cones, and uncover a molecular heterogeneity whereby different filopodia display markedly different responses to changes in the accumulation of ENA and VASP fluorescence in their tips over time.

scholarly journals Systematic functional characterization of antisense eRNA of protocadherin α composite enhancer

2021 ◽  
Vol 35 (19-20) ◽  
pp. 1383-1394
Author(s):  
Yuxiao Zhou ◽  
Siyuan Xu ◽  
Mo Zhang ◽  
Qiang Wu
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Functional Characterization ◽  
Three Dimensional ◽  
Elongation Factor ◽  
Locked Nucleic Acid ◽  
Loop Formation ◽  
Long Distance ◽  
Enhancer Region

Enhancers generate bidirectional noncoding enhancer RNAs (eRNAs) that may regulate gene expression. At present, the eRNA function remains enigmatic. Here, we report a 5′ capped antisense eRNA PEARL (Pcdh eRNA associated with R-loop formation) that is transcribed from the protocadherin (Pcdh) α HS5-1 enhancer region. Through loss- and gain-of-function experiments with CRISPR/Cas9 DNA fragment editing, CRISPRi, and CRISPRa, as well as locked nucleic acid strategies, in conjunction with ChIRP, MeDIP, DRIP, QHR-4C, and HiChIP experiments, we found that PEARL regulates Pcdhα gene expression by forming local RNA–DNA duplexes (R-loops) in situ within the HS5-1 enhancer region to promote long-distance chromatin interactions between distal enhancers and target promoters. In particular, increased levels of eRNA PEARL via perturbing transcription elongation factor SPT6 lead to strengthened local three-dimensional chromatin organization within the Pcdh superTAD. These findings have important implications regarding molecular mechanisms by which the HS5-1 enhancer regulates stochastic Pcdhα promoter choice in single cells in the brain.

Comparison of gene expression and activation of transcription factors in organoid-derived monolayer intestinal epithelial cells and organoids

2021 ◽  
Author(s):  
Yu Takahashi ◽  
Yu Inoue ◽  
Keitaro Kuze ◽  
Shintaro Sato ◽  
Makoto Shimizu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Gene Expression Regulation ◽  
Intestinal Epithelial Cells ◽  
Three Dimensional ◽  
Culture Conditions ◽  
Dependent Manner ◽  
Intestinal Epithelial

Abstract Intestinal organoids better represent in vivo intestinal properties than conventionally used established cell lines in vitro. However, they are maintained in three-dimensional culture conditions that may be accompanied by handling complexities. We characterized the properties of human organoid-derived two-dimensionally cultured intestinal epithelial cells (IECs) compared with those of their parental organoids. We found that the expression of several intestinal markers and functional genes were indistinguishable between monolayer IECs and organoids. We further confirmed that their specific ligands equally activate intestinal ligand-activated transcriptional regulators in a dose-dependent manner. The results suggest that culture conditions do not significantly influence the fundamental properties of monolayer IECs originating from organoids, at least from the perspective of gene expression regulation. This will enable their use as novel biological tools to investigate the physiological functions of the human intestine.

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