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Pia Bernasconi, Nicola Carboni, Giulia Ricci, Gabriele Siciliano, Luisa Politano, Lorenzo Maggi, Tiziana Mongini, Liliana Vercelli, Carmelo Rodolico, Elena Biagini, Giuseppe Boriani, Lucia Ruggiero, Lucio Santoro, Elisa Schena, Sabino Prencipe, Camilla Evangelisti, Elena Pegoraro, Lucia Morandi, Marta Columbaro, Chiara Lanzuolo, Patrizia Sabatelli, Paola Cavalcante, Cristina Cappelletti, Gisèle Bonne, Antoine Muchir, Giovanna Lattanzi
Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients...
April 25, 2018: Nucleus
Simona Graziano, Ray Kreienkamp, Nuria Coll-Bonfill, Susana Gonzalo
Mammalian nuclei are equipped with a framework of intermediate filaments that function as a karyoskeleton. This nuclear scaffold, formed primarily by lamins (A-type and B-type), maintains the spatial and functional organization of the genome and of sub-nuclear compartments. Over the past decade, a body of evidence has highlighted the significance of these structural nuclear proteins in the maintenance of nuclear architecture and mechanical stability, as well as genome function and integrity. The importance of these structures is now unquestioned given the wide range of degenerative diseases that stem from LMNA gene mutations, including muscular dystrophy disorders, peripheral neuropathies, lipodystrophies, and premature aging syndromes...
April 11, 2018: Nucleus
Agnieszka Madej-Pilarczyk
Emery-Dreifuss muscular dystrophy (EDMD), clinically characterized scapulo-humero-peroneal muscle atrophy and weakness, multi-joint contractures with spine rigidity and cardiomyopathy with conduction defects, is associated with structural/functional defect of genes that encode the proteins of nuclear envelope, including lamin A and several lamin-interating proteins. This paper presents clinical aspects of EDMD in context to causative genes, genotype-phenotype correlation and its emplacement within phenotypic spectrum of skeletal muscle diseases associated with envelopathies...
April 10, 2018: Nucleus
Bianchi Andrea, Manti Pierluigi Giuseppe, Lucini Federica, Lanzuolo Chiara
The alteration of the several roles that Lamin A/C plays in the mammalian cell leads to a broad spectrum of pathologies that - all together - are named laminopathies. Among those, the Emery Dreifuss Muscular Dystrophy (EDMD) is of particular interest as, despite the several known mutations of Lamin A/C, the genotype-phenotype correlation still remains poorly understood; this suggests that the epigenetic background of patients might play an important role during the time course of the disease. Historically, both a mechanical role of Lamin A/C and a regulative one have been suggested as the driving force of Laminopathies; however, those two hypotheses are not mutually exclusive...
April 5, 2018: Nucleus
Karim Harhouri, Diane Frankel, Catherine Bartoli, Patrice Roll, Annachiara De Sandre-Giovannoli, Nicolas Lévy
Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin...
April 5, 2018: Nucleus
Sangkyun Cho, Amal Abbas, Jerome Irianto, Irena Ivanovska, Yuntao Xia, Manu Tewari, Dennis E Discher
Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs)...
April 5, 2018: Nucleus
Koichi Utani, Mirit I Aladjem
Since the discovery of a yeast gene silencing modifier (Silent Information Modifier 2, SIR2) and its role in maintaining genomic stability more than two decades ago, SIR2 homologs (sirtuins) were identified in diverse species. Sirtuins are protein deacetylases that play diverse roles in proper cellular metabolism including cell cycle progression and maintenance of genomic stability. In yeast, SIR2 interacts with replication origins and protein complexes that affect both replication origin usage and gene silencing...
March 26, 2018: Nucleus
Cristina Guillín-Amarelle, Antía Fernández-Pombo, Sofía Sánchez-Iglesias, David Araújo-Vilar
The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies)...
March 20, 2018: Nucleus
Ryszard Rzepecki, Yosef Gruenbaum
Lamins are evolutionarily conserved nuclear intermediate filament proteins. They provide structural support for the nucleus and help regulate many other nuclear activities. Mutations in human lamin genes, and especially in the LMNA gene, cause numerous diseases, termed laminopathies, including muscle, cardiac, metabolic, neuronal and early aging diseases. Most laminopathies arise from autosomal dominant missense mutations. Many of the mutant residues are conserved in the lamin genes of the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster...
March 20, 2018: Nucleus
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No abstract text is available yet for this article.
January 1, 2018: Nucleus
Corinne Vigouroux, Anne-Claire Guénantin, Camille Vatier, Emilie Capel, Caroline Le Dour, Pauline Afonso, Guillaume Bidault, Véronique Béréziat, Olivier Lascols, Jacqueline Capeau, Nolwenn Briand, Isabelle Jéru
Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure...
January 1, 2018: Nucleus
Nolwenn Briand, Philippe Collas
The nuclear lamina contributes to the regulation of gene expression and to chromatin organization. Mutations in A-type nuclear lamins cause laminopathies, some of which are associated with a loss of heterochromatin at the nuclear periphery. Until recently however, little if any information has been provided on where and how lamin A interacts with the genome and on how disease-causing lamin A mutations may rearrange genome conformation. Here, we review aspects of nuclear lamin association with the genome. We highlight recent evidence of reorganization of lamin A-chromatin interactions in cellular models of laminopathies, and implications on the 3-dimensional rearrangement of chromatin in these models, including patient cells...
January 1, 2018: Nucleus
Shalaka Chitale, Holger Richly
The integrity of the genome is maintained by specific DNA repair pathways. The main pathway removing DNA lesions induced by exposure to UV light is nucleotide excision repair (NER). The DNA damage response at chromatin is accompanied by the recruitment of DNA repair factors to the lesion site and the deposition of specific histone marks. The function of these histone marks in NER stays for the most part elusive. We have recently reported that the methyltransferase MMSET catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2) at the lesion site...
January 1, 2018: Nucleus
Mohammad Soheilypour, Mohammad R K Mofrad
Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how quality control proteins at the entry of the nuclear pore complex (NPC) distinguish normal and aberrant mRNAs. While some of the involved components are suggested to act as switches and recruit different factors to normal versus aberrant mRNAs, some experimental and computational evidence suggests that the combined effect of the regulated stochastic interactions between the involved components could potentially achieve an efficient quality control of mRNAs...
January 1, 2018: Nucleus
David Lando, Tim J Stevens, Srinjan Basu, Ernest D Laue
Single-cell chromosome conformation capture approaches are revealing the extent of cell-to-cell variability in the organization and packaging of genomes. These single-cell methods, unlike their multi-cell counterparts, allow straightforward computation of realistic chromosome conformations that may be compared and combined with other, independent, techniques to study 3D structure. Here we discuss how single-cell Hi-C and subsequent 3D genome structure determination allows comparison with data from microscopy...
January 1, 2018: Nucleus
Jekaterina Erenpreisa, Jekabs Krigerts, Kristine Salmina, Turs Selga, Hermanis Sorokins, Talivaldis Freivalds
The chromatin observed by conventional electron microscopy under the nuclear envelope constitutes a single layer of dense 30-35 nm granules, while ∼30 nm fibrils laterally attached to them, form large patches of lamin-associated domains (LADs). This particular surface "epichromatin" can be discerned by specific (H2A+H2B+DNA) conformational antibody at the inner nuclear envelope and around mitotic chromosomes. In order to differentiate the DNA conformation of the peripheral chromatin we applied an Acridine orange (AO) DNA structural test involving RNAse treatment and the addition of AO after acid pre-treatment...
January 1, 2018: Nucleus
C A Brackley, J Johnson, D Michieletto, A N Morozov, M Nicodemi, P R Cook, D Marenduzzo
Chromatin loop extrusion is a popular model for the formation of CTCF loops and topological domains. Recent HiC data have revealed a strong bias in favour of a particular arrangement of the CTCF binding motifs that stabilize loops, and extrusion is the only model to date which can explain this. However, the model requires a motor to generate the loops, and although cohesin is a strong candidate for the extruding factor, a suitable motor protein (or a motor activity in cohesin itself) has yet to be found. Here we explore a new hypothesis: that there is no motor, and thermal motion within the nucleus drives extrusion...
January 1, 2018: Nucleus
Aleksander Szczurek, Udo Birk, Hans Knecht, Jurek Dobrucki, Sabine Mai, Christoph Cremer
Methods of super-resolving light microscopy (SRM) have found an exponentially growing range of applications in cell biology, including nuclear structure analyses. Recent developments have proven that Single Molecule Localization Microscopy (SMLM), a type of SRM, is particularly useful for enhanced spatial analysis of the cell nucleus due to its highest resolving capability combined with very specific fluorescent labeling. In this commentary we offer a brief review of the latest methodological development in the field of SMLM of chromatin designated DNA Structure Fluctuation Assisted Binding Activated Localization Microscopy (abbreviated as fBALM) as well as its potential future applications in biology and medicine...
January 1, 2018: Nucleus
Lukasz Majewski, Jolanta Nowak, Magdalena Sobczak, Olena Karatsai, Serhiy Havrylov, Robert Lenartowski, Malgorzata Suszek, Marta Lenartowska, Maria Jolanta Redowicz
Myosin VI (MVI) is a unique actin-based motor protein moving towards the minus end of actin filaments, in the opposite direction than other known myosins. Besides well described functions of MVI in endocytosis and maintenance of Golgi apparatus, there are few reports showing its involvement in transcription. We previously demonstrated that in neurosecretory PC12 cells MVI was present in the cytoplasm and nucleus, and its depletion caused substantial inhibition of cell migration and proliferation. Here, we show an increase in nuclear localization of MVI upon cell stimulation, and identification of potential nuclear localization (NLS) and nuclear export (NES) signals within MVI heavy chain...
January 1, 2018: Nucleus
Evgeny Smirnov, Matúš Hornáček, Tomáš Vacík, Dušan Cmarko, Ivan Raška
Numerous studies based on new single-cell and single-gene techniques show that individual genes can be transcribed in short bursts or pulses accompanied by changes in pulsing frequencies. Since so many examples of such discontinuous or fluctuating transcription have been found from prokaryotes to mammals, it now seems to be a common mode of gene expression. In this review we discuss the occurrence of the transcriptional fluctuations, the techniques used for their detection, their putative causes, kinetic characteristics, and probable physiological significance...
January 1, 2018: Nucleus
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