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James R. Davie - One of the best experts on this subject based on the ideXlab platform.
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The insulator binding protein CTCF associates with the Nuclear Matrix.
Experimental Cell Research, 2003Co-Authors: Katherine L. Dunn, Helen Zhao, James R. DavieAbstract:Nuclear DNA is organized into chromatin loop domains. At the base of these loops, Matrix-associated regions (MARs) of the DNA interact with Nuclear Matrix proteins. MARs act as structural boundaries within chromatin, and MAR binding proteins may recruit multiprotein complexes that remodel chromatin. The potential tumor suppressor protein CTCF binds to vertebrate insulators and is required for insulator activity. We demonstrate that CTCF is associated with the Nuclear Matrix and can be cross-linked to DNA by cisplatin, an agent that preferentially cross-links Nuclear Matrix proteins to DNA in situ. These results suggest that CTCF anchors chromatin to the Nuclear Matrix, suggesting that there is a functional connection between insulators and the Nuclear Matrix. We also show that the chromatin-modifying enzymes HDAC1 and HDAC2, which are intrinsic Nuclear Matrix components and thought to function as corepressors of CTCF, are incapable of associating with CTCF. Hence, the insulator activity of CTCF apparently involves an HDAC-independent association with the Nuclear Matrix. We propose that CTCF may demarcate Nuclear Matrix-dependent points of transition in chromatin, thereby forming topologically independent chromatin loops that may support gene silencing.
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Nuclear Matrix, dynamic histone acetylation and transcriptionally active chromatin
Molecular biology reports, 1997Co-Authors: James R. DavieAbstract:The Nuclear Matrix, the RNA-protein skeleton of the nucleus, has a role in the organization and function of Nuclear DNA. Nuclear processes associated with the Nuclear Matrix include transcription, replication and dynamic histone acetylation. Nuclear Matrix proteins, which are tissue and cell type specific, are altered with transformation and state of differentiation. Transcription factors are associated with the Nuclear Matrix, with the spectra of Nuclear Matrix bound factors being cell type specific. There is compelling evidence that the transcription machinery is anchored to the Nuclear Matrix, and the chromatin fiber is spooled through this complex. Transcriptionally active chromatin domains are associated with dynamically acetylated histones. The energy exhaustive process of dynamic histone acetylation has several functions. Acetylation of the N-terminal tails of the core histones alters nucleosome and higher order chromatin structure, aiding transcriptional elongation and facilitating the binding of transcription factors to nucleosomes associated with regulatory DNA sequences. Histone acetylation can manipulate the interactions of regulatory proteins that bind to the N-terminal tails of the core histones. Lastly, dynamic acetylation may contribute to the transient attachment of transcriptionally active chromatin to the Nuclear Matrix. Reversible histone acetylation is catalyzed by histone acetyltransferase and deacetylase, enzymes associated with the Nuclear Matrix. The recent isolation and characterization of histone acetyltransferase and deacetylase reveals that these enzymes are related to transcriptional regulators, providing us with new insights about how these enzymes are targeted to Nuclear Matrix sites engaged in transcription.
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Histone modifications, chromatin structure, and the Nuclear Matrix.
Journal of cellular biochemistry, 1996Co-Authors: James R. DavieAbstract:The Nuclear Matrix has a role in the organization and function of Nuclear DNA. A combination of stable and transient interactions between chromatin and the Nuclear Matrix is involved in organizing DNA within the nucleus. DNA sequences (Matrix attachment regions) at the base of a loop bind to Nuclear Matrix proteins and arrange the Nuclear DNA into chromatin loop domains. Multiple, transient interactions between the Nuclear Matrix and transcriptionally active chromatin are thought to be responsible for the insoluble feature of transcriptionally active chromatin. Current evidence suggests that histone acetyltransferase, histone deacetylase (enzymes that catalyze rapid histone acetylation and deacetylation), transcription factors, and the transcription machinery mediate the transient attachments between Nuclear Matrix and active chromatin. Highly acetylated core histones, which are associated with transcriptionally active DNA, are also ubiquitinated and phosphorylated. Recent studies show that specific H1 subtypes and their phosphorylated isoforms are localized in centers of RNA splicing in the nucleus. The implications of these findings and the impact of the histone modifications on the Nuclear-organization of chromatin are discussed.
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The Nuclear Matrix and the Regulation of Chromatin Organization and Function
International review of cytology, 1995Co-Authors: James R. DavieAbstract:Nuclear DNA is organized into loop domains, with the base of the loop being bound to the Nuclear Matrix. Loops with transcriptionally active and/or potentially active genes have a DNase I-sensitive chromatin structure, while repressed chromatin loops have a condensed configuration that is essentially invisible to the transcription machinery. Core histone acetylation and torsional stress appear to be responsible for the generation and/or maintenance of the open potentially active chromatin loops. The transcriptionally active region of the loop makes several dynamic attachments with the Nuclear Matrix and is associated with core histones that are dynamically acetylated. Histone acetyltransferase and deacetylase, which catalyze this rapid acetylation and deacetylation, are bound to the Nuclear Matrix. Several transcription factors are components of the Nuclear Matrix. Histone acetyltransferase, deacetylase, and transcription factors may contribute to the dynamic attachment of the active chromatin domains with the Nuclear Matrix at sites of ongoing transcription.
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Histone acetyltransferase is associated with the Nuclear Matrix.
The Journal of biological chemistry, 1994Co-Authors: M J Hendzel, Jian-min Sun, Hou Yu Chen, J. B. Rattner, James R. DavieAbstract:Abstract Only a small fraction of the adult chicken erythrocyte histones is involved in dynamic acetylation. We have reported previously that the rapidly acetylated and deacetylated H4 histones are primarily associated with the transcriptionally active DNA-enriched chromatin fragments that remain attached to the residual Nuclear material following micrococcal nuclease digestion and chromatin solubilization. Furthermore, this Nuclear fraction contained most of the histone deacetylase activity. In this study we show that the bulk of the Nuclear histone acetyltransferase activity is located with the insoluble residual Nuclear material. We demonstrate that in vitro the enzymes associated with the residual Nuclear material catalyze reversible acetylation when the endogenous histones of the Nuclear skeleton-bound chromatin fragments are used as substrate. Nuclear matrices isolated from adult chicken immature erythrocyte and trout liver nuclei had 60-76% of the Nuclear histone acetyltransferase activity. Procedures that solubilized the internal Nuclear Matrix also resulted in the release of the enzyme from the Nuclear Matrix. Together, our observations suggest that histone acetyltransferase and deacetylase are associated with the internal Nuclear Matrix, and one of the functions of these enzymes may be to mediate a dynamic attachment between transcriptionally active chromatin and the Nuclear Matrix.
Thomas C. Spelsberg - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Matrix and steroid hormone action.
Vitamins and hormones, 1999Co-Authors: Thomas J. Barrett, Thomas C. SpelsbergAbstract:Publisher Summary This chapter describes the different aspects of Nuclear Matrix and steroid hormone action. The Nuclear Matrix has been shown to have a role in DNA organization, replication, transcription, and the processing of messenger RNA (mRNA) and possibly intraNuclear signaling for the regulation of gene transcription. The Nuclear Matrix has been implicated in the actions of steroid hormones on gene expression. The eucaryotic nucleus can be thought of as a highly ordered, compartmentalized organelle. Classical ultrastructural studies have demonstrated that the cell nucleus is an elaborate structure composed of regions of chromatin, which includes the DNA bound with a variety of proteins and attached to a nonchromatin infrastructure of nucleoprotein fibrillary network, which includes the Nuclear Matrix. The major component of isolated matrices is a multitude of different proteins with an enrichment of the higher molecular weight nonhistone proteins in the nucleus and a depletion of low-molecular-weight proteins, especially the histones. Chromosome structure and Nuclear Matrix interaction appear to be important in steroid hormone-mediated transcriptional control. A convergence of biochemical and genetic studies has identified several ATP-dependent multiprotein complexes that may help transcriptional activators overcome chromatin-mediated repression.
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Nuclear Matrix Acceptor Binding Sites for Steroid Hormone Receptors: A Candidate Nuclear Matrix Acceptor Protein
International review of cytology, 1995Co-Authors: Andrea H. Lauber, Nicole P. Sandhu, Mark Schuchard, Malayannan Subramaniam, Thomas C. SpelsbergAbstract:Steroid/Nuclear-hormone receptors are ligand-activated transcription factors that have been localized to the Nuclear Matrix. The classic model of hormone action suggests that, following activation, these receptors bind to specific „steroid response elements” on the DNA, then interact with other factors in the transcription initiation complex. However, evidence demonstrates the existence of specific chromatin proteins that act as accessory factors by facilitating the binding of the steroid receptors to the DNA. One such protein, the „receptor binding factor (RBF)-1 ”, has been purified and shown to confer specific, high-affinity binding of the progesterone receptor to the DNA. Interestingly, the RBF-1 is localized to the Nuclear Matrix. Further, the RBF-1 binds specifically to a sequence of the c-myc proto-oncogene that has the appearance of a Nuclear Matrix attached region (MAR). These results, and other findings reviewed here, suggest that the Nuclear Matrix is involved intimately in steroid hormone-regulated gene expression.
T De Lange - One of the best experts on this subject based on the ideXlab platform.
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structure subNuclear distribution and Nuclear Matrix association of the mammalian telomeric complex
Journal of Cell Biology, 1996Co-Authors: M E Luderus, B Van Steensel, Laura Chong, Ody C M Sibon, Fons Cremers, T De LangeAbstract:Mammalian telomeres are composed of long arrays of TTAGGG repeats complexed with the TTAGGG repeat binding factor, TRF. Biochemical and ultrastructural data presented here show that the telomeric DNA and TRF colocalize in individual, condensed structures in the Nuclear Matrix. Telomeric TTAGGG repeats were found to carry an array of Nuclear Matrix attachment sites occurring at a frequency of at least one per kb. The Nuclear Matrix association of the telomeric arrays extended over large domains of up to 20-30 kb, encompassing the entire length of most mammalian telomeres. TRF protein and telomeric DNA cofractionated in Nuclear Matrix preparations and colocalized in discrete, condensed sites throughout the Nuclear volume. FISH analysis indicated that TRF is an integral component of the telomeric complex and that the presence of TRF on telomeric DNA correlates with the compact configuration of telomeres and their association with the Nuclear Matrix. Biochemical fractionation of TRF and telomeric DNA did not reveal an interaction with the Nuclear lamina. Furthermore, ultrastructural analysis indicated that the mammalian telomeric complex occupied sites throughout the Nuclear volume, arguing against a role for the Nuclear envelope in telomere function during interphase. These results are consistent with the view that mammalian telomeres form Nuclear Matrix-associated, TRF-containing higher order complexes at dispersed sites throughout the Nuclear volume.
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Human telomeres are attached to the Nuclear Matrix.
The EMBO journal, 1992Co-Authors: T De LangeAbstract:This report shows that human telomeres are tightly associated with the Nuclear Matrix. Telomere attachment is observed in several cell types and in all stages of interphase. Mapping experiments show that telomeres are anchored via their TTAGGG repeats; a subtelomeric repeat located immediately proximal to the telomeric TTAGGG repeats is quantitatively released from the Nuclear Matrix by restriction endonuclease cleavage. TTAGGG repeats introduced at chromosome-internal sites by DNA transfection do not behave as Matrix attached loci, suggesting that the telomeric position of the repeats is required for their interaction with the Nuclear Matrix. These findings are consistent with the idea that telomeres function as a nucleoprotein complex.
Robert H. Getzenberg - One of the best experts on this subject based on the ideXlab platform.
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Association of transcription factors with the Nuclear Matrix.
Journal of cellular biochemistry, 1996Co-Authors: Tisha A. Nardozza, Martha M. Quigley, Robert H. GetzenbergAbstract:The Nuclear Matrix is the framework scaffolding of the nucleus and has been demonstrated to be an important component in a number of Nuclear processes including transcription, replication, and RNA splicing and transport. In the interphase nucleus, DNA is specifically organized in a three-dimensional fashion. An example of this fact is that actively transcribed genes have been demonstrated to associate with the Nuclear Matrix. In this study, Nuclear Matrix proteins from various rat tissues, including two androgen-regulated tissues, the seminal vesicle and ventral prostate, were examined to determine if they contained proteins that associate with consensus binding sequences for several proteins involved in the regulation of transcription. Specific interactions were identified between proteins of the Nuclear Matrix and these transcriptional activator binding sequences. In addition, the sizes of the complexes binding to the DNA sequences appeared to vary in some of the tissues. These data support the concept that the Nuclear Matrix may serve as a support structure to bring together specific DNA sequences with factors involved in the regulation of gene expression.
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bladder cancer associated Nuclear Matrix proteins
Cancer Research, 1996Co-Authors: Robert H. Getzenberg, Martha M. Quigley, Badrinath R Konety, Theresa A Oeler, Ardeshir Hakam, Michael J Becich, Robert R BahnsonAbstract:The early diagnosis of bladder cancer is central to the effective treatment of the disease. Presently, there are no methods available to easily and specifically identify the presence of bladder cancer cells. The prevailing method for the detection of bladder cancer is the identification of bladder cancer cells by morphological examination of exfoliated cells or biopsy material by a pathologist. A hallmark of the malignant or transformed phenotype is an abnormal Nuclear shape, the presence of multiple nucleoli, and altered patterns of chromatin organization. Nuclear structural alterations are so prevalent in cancer cells that they are commonly used as markers of transformation for many types of cancer. Nuclear shape is determined by the Nuclear Matrix, the dynamic skeleton of the nucleus. The Nuclear Matrix is the structural component of the nucleus that determines Nuclear morphology, organizes the DNA in a three-dimensional fashion that is tissue specific, and has a central role in the regulation of a number of Nuclear processes, including the regulation of DNA replication and gene expression. Previous investigations into prostate and breast cancer have revealed that Nuclear Matrix protein (NMP) composition undergoes alterations with transformation and that the Nuclear Matrix can serve as a marker for the malignant phenotype. In this study, we have identified NMPs with which it is possible to differentiate human bladder tumors from normal bladder epithelial cells. We examined the NMP composition of 17 matched tumor and normal samples from patients undergoing surgery for bladder cancer. We have identified six proteins present in all tumor samples that are not present in the corresponding normal samples and three proteins that are unique to the normal bladder tissues in comparison with the tumor samples. Five of the six bladder cancer-associated proteins were also identified in three human bladder cancer cell lines examined (253j, UMUC-2, and T24). Therefore, we have demonstrated that Nuclear Matrix composition is able to differentiate bladder cancer from normal bladder tissue and may provide useful tools for early detection and recurrence of the disease. Importantly, these markers may provide valuable tools for cytopathological screening for bladder carcinoma.
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The Utilization of Nuclear Matrix Proteins for Cancer Diagnosis
Critical reviews in eukaryotic gene expression, 1996Co-Authors: Tracy S. Replogle-schwab, Kenneth J. Pienta, Robert H. GetzenbergAbstract:There is a great need for improved biomarkers in the areas of cancer diagnosis and treatment. Cancer-specific Nuclear Matrix proteins may provide clinicians with improved biomarkers for earlier diagnosis as well as improved therapies. The Nuclear Matrix is the RNA-protein skeleton of the nucleus that has structural and functional roles within the cell. Nuclear Matrix proteins of a variety of cell lines and tissues, both normal and cancerous, have now been examined and are beginning to be characterized. After comparison of tumor and normal tissues as well as distinct tissue-specific and cancer-specific differences. It is these proteins differences that provide possible biomarkers that may allow for earlier detection of cancer and thus potentially increase the chance of survival.
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Identification of Nuclear Matrix proteins in the cancer and normal rat prostate.
Cancer research, 1991Co-Authors: Robert H. Getzenberg, Kenneth J. Pienta, Edwin Y. W. Huang, Donald S. CoffeyAbstract:Abstract The Nuclear Matrix is the structural component of the nucleus that determines Nuclear morphology and organizes the DNA in a three-dimensional fashion that is tissue specific. Previously, some of the Nuclear Matrix proteins have been reported to the both tissue and cell type specific and are altered with the state of differentiation and transformation. This study demonstrates that the Nuclear Matrix is specific for the individual lobes of the normal rat prostate and that the Nuclear Matrix undergoes changes in protein composition in the Dunning prostate cancer tissue. Additionally, in the Dunning rat prostate adenocarcinoma cell lines, there is a range of tumor phenotypes and the Nuclear Matrix varies in composition in each tumor cell type. These differences in the Nuclear Matrix proteins are associated with quantitative changes in Nuclear morphology that form the pleiomorphic state of the cancer nucleus.
Jeffrey A. Nickerson - One of the best experts on this subject based on the ideXlab platform.
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Identifying Nuclear Matrix-Attached DNA Across the Genome.
Journal of cellular physiology, 2017Co-Authors: Jason R. Dobson, Jeffrey A. Nickerson, Deli Hong, A. Rasim Barutcu, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Andre J. Van Wijnen, Gary S. SteinAbstract:Experimental approaches to define the relationship between gene expression and Nuclear Matrix attachment regions (MARs) have given contrasting and method-specific results. We have developed a next generation sequencing strategy to identify MARs across the human genome (MAR-Seq). The method is based on crosslinking chromatin to its Nuclear Matrix attachment sites to minimize changes during biochemical processing. We used this method to compare Nuclear Matrix organization in MCF-10A mammary epithelial-like cells and MDA-MB-231 breast cancer cells and evaluated the results in the context of global gene expression (array analysis) and positional enrichment of gene-regulatory histone modifications (ChIP-Seq). In the normal-like cells, Nuclear Matrix-attached DNA was enriched in expressed genes, while in the breast cancer cells, it was enriched in non-expressed genes. In both cell lines, the chromatin modifications that mark transcriptional activation or repression were appropriately associated with gene expression. Using this new MAR-Seq approach, we provide the first genome-wide characterization of Nuclear Matrix attachment in mammalian cells and reveal that the Nuclear Matrix-associated genome is highly cell-context dependent. J. Cell. Physiol. 232: 1295-1305, 2017. © 2016 Wiley Periodicals, Inc.
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Experimental observations of a Nuclear Matrix
Journal of Cell Science, 2001Co-Authors: Jeffrey A. NickersonAbstract:Nuclei are intricately structured, and Nuclear metabolism has an elaborate spatial organization. The architecture of the nucleus includes two overlapping and nucleic-acid-containing structures - chromatin and a Nuclear Matrix. The Nuclear Matrix is observed by microscopy in live, fixed and extracted cells. Its ultrastructure and composition show it to be, in large part, the ribonucleoprotein (RNP) network first seen in unfractionated cells more than 30 years ago. At that time, the discovery of this RNP structure explained surprising observations that RNA, packaged in proteins, is attached to an intraNuclear, non-chromatin structure. Periodic and specific attachments of chromatin fibers to the Nuclear Matrix create the chromatin loop domains that can be directly observed by microscopy or inferred from biochemical experiments. The ultrastructure of the Nuclear Matrix is well characterized and consists of a Nuclear lamina and an internal Nuclear network of subassemblies linked together by highly structured fibers. These complex fibers are built on an underlying scaffolding of branched 10-nm filaments that connect to the Nuclear lamina. The structural proteins of the Nuclear lamina have been well characterized, but the structural biochemistry of the internal Nuclear Matrix has received less attention. Many internal Matrix proteins have been identified, but far less is known about how these proteins assemble to make the fibers, filaments and other assemblies of the internal Nuclear Matrix. Correcting this imbalance will require the combined application of biochemistry and electron microscopy. The central problem in trying to define Nuclear Matrix structure is to identify the proteins that assemble into the 10-nm filaments upon which the interior architecture of the nucleus is constructed. Only by achieving a biochemical characterization of the Nuclear Matrix will we advance beyond simple microscopic observations of structure to a better understanding of Nuclear Matrix function, regulation and post-mitotic assembly.
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The Nuclear Matrix prepared by amine modification
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Katherine M. Wan, Jeffrey A. Nickerson, Gabriela Krockmalnic, Sheldon PenmanAbstract:The nucleus is spatially ordered by attachments to a nonchromatin Nuclear structure, the Nuclear Matrix. The Nuclear Matrix and chromatin are intimately connected and integrated structures, and so a major technical challenge in Nuclear Matrix research has been to remove chromatin while retaining a native Nuclear Matrix. Most methods for removing chromatin require first a nuclease digestion and then a salt extraction to remove cut chromatin. We have hypothesized that cut chromatin is held in place by charge interactions involving nucleosomal amino groups. We have tested this hypothesis by chemically modifying amino groups after nuclease digestion. By using this protocol, chromatin could be effectively removed at physiological ionic strength. We compared the ultrastructure and composition of this Nuclear Matrix preparation with the traditional high-salt Nuclear Matrix and with the third Nuclear Matrix preparation that we have developed from which chromatin is removed after extensive crosslinking. All three Matrix preparations reveal internal Nuclear Matrix structures that are built on a network of branched filaments of about 10 nm diameter. That such different chromatin-removal protocols reveal similar principles of Nuclear Matrix construction increases our confidence that we are observing important architectural elements of the native structure in the living cell.
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The Nuclear Matrix: Past and Present
Nuclear Structure and Gene Expression, 1997Co-Authors: Sheldon Penman, Benjamin J. Blencowe, Jeffrey A. NickersonAbstract:Publisher Summary This chapter describes the structure and function of the Nuclear Matrix. The Nuclear Matrix is firmly connected to the extensive network of intermediate filaments occupying the cytoplasmic space and anchoring on the outer surface of the Nuclear lamina. The Nuclear Matrix and intermediate filaments are integrated into a single cell-wide structure that retains the overall geometry and appearance of the intact cell. Changes in Nuclear Matrix protein composition have also been observed during development. The fetal rat calvarial osteoblast has become an important in vitro developmental system for studying phenotype-specific gene expression. Six Nuclear Matrix proteins have been reported in human colon adenocarcinoma tumor samples which were absent from normal colon tissue. Such malignancy-specific Nuclear Matrix proteins may have considerable diagnostic value and may help to explain the changes in Nuclear structure that accompany malignancy. The studies on rat osteosarcoma cells suggested that these tumor cells are expressing Matrix proteins normally expressed only at earlier developmental stages in the osteoblast lineage.
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The Nuclear Matrix protein NMP-1 is the transcription factor YY1
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Bo Guo, Sheldon Penman, Jeffrey A. Nickerson, Janet L. Stein, Paul R. Odgren, A J Van Wijnen, J. B. Lian, Gary S. SteinAbstract:Abstract NMP-1 was initially identified as a Nuclear Matrix-associated DNA-binding factor that exhibits sequence-specific recognition for the site IV regulatory element of a histone H4 gene. This distal promoter domain is a Nuclear Matrix interaction site. In the present study, we show that NMP-1 is the multifunctional transcription factor YY1. Gel-shift and Western blot analyses demonstrate that NMP-1 is immunoreactive with YY1 antibody. Furthermore, purified YY1 protein specifically recognizes site IV and reconstitutes the NMP-1 complex. Western blot and gel-shift analyses indicate that YY1 is present within the Nuclear Matrix. In situ immunofluorescence studies show that a significant fraction of YY1 is localized in the Nuclear Matrix, principally but not exclusively associated with residual nucleoli. Our results confirm that NMP-1/YY1 is a ubiquitous protein that is present in both human cells and in rat osteosarcoma ROS 17/2.8 cells. The finding that NMP-1 is identical to YY1 suggests that this transcriptional regulator may mediate gene-Matrix interactions. Our results are consistent with the concept that the Nuclear Matrix may functionally compartmentalize the eukaryotic nucleus to support regulation of gene expression.
