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Lamin associated domain

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...
March 8, 2018: Nucleus
Can Zhou, Li Rao, Catherine M Shanahan, Qiuping Zhang
Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Nesprin-1 and -2 are highly expressed in skeletal and cardiac muscles and together with SUN (Sad1p/UNC84) domain-containing proteins form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex at the nuclear envelope in association with lamin A/C and emerin. Mutations in nesprin-1/2 have been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM)...
February 27, 2018: Biochemical Society Transactions
Holly Whitton, Larry N Singh, Marissa A Patrick, Andrew J Price, Fernando G Osorio, Carlos López-Otín, Irina M Bochkis
Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors...
February 27, 2018: Aging Cell
Angela Palmigiano, Francesco Santaniello, Aurora Cerutti, Dmitry Penkov, Divya Purushothaman, Ekta Makhija, Lucilla Luzi, Fabrizio d'Adda di Fagagna, Pier Giuseppe Pelicci, Viveswara Shivashankar, Gaetano Ivan Dellino, Francesco Blasi
The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase. The targeted DNA sequences correspond to Lamin-Associated Domains (LADs), and include late-replicating (LRRs) and temporal transition regions (TTRs)...
February 16, 2018: Scientific Reports
Emilie Lukášová, Aleš Kovařík, Stanislav Kozubek
Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin domains (termed LAD) and simultaneously bind either lamin A/C or lamin B1. One of these proteins is the lamin B receptor (LBR) that binds lamin B1 and tethers heterochromatin to the INM in embryonic and undifferentiated cells...
February 6, 2018: Cells
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 24, 2018: Nucleus
Carol C L Chen, Preeti Goyal, Mohammad M Karimi, Marie H Abildgaard, Hiroshi Kimura, Matthew C Lorincz
Phosphorylation of histone H3 at serine 10 (H3S10ph) by Aurora kinases plays an important role in mitosis; however, H3S10ph also marks regulatory regions of inducible genes in interphase mammalian cells, implicating mitosis-independent functions. Using the fluorescent ubiquitin-mediated cell cycle indicator (FUCCI), we found that 30% of the genome in interphase mouse embryonic stem cells (ESCs) is marked with H3S10ph. H3S10ph broadly demarcates gene-rich regions in G1 and is positively correlated with domains of early DNA replication timing (RT) but negatively correlated with H3K9me2 and lamin-associated domains (LADs)...
January 2018: Genome Research
Ksenia Perepelina, Renata I Dmitrieva, Elena Ignatieva, Aleksandra Borodkina, Anna Kostareva, Anna Malashicheva
Lamin A/C is involved in many cellular functions due to its ability to bind chromatin and transcription factors and affect their properties. Mutations of LMNA gene encoding lamin A/C affect differentiation capacity of stem cells. However, signaling pathways involved in interaction with lamins in cellular differentiation remain unclear. Lipodystrophy associated with LMNA mutation R482L causes loss of fat tissue. In this study we investigated the role of LMNA mutation R482L in modulating Notch signaling activity in adipogenic differentiation of mesenchymal stem cells...
October 17, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Farbod Sedaghat-Hamedani, Jan Haas, Feng Zhu, Christian Geier, Elham Kayvanpour, Martin Liss, Alan Lai, Karen Frese, Regina Pribe-Wolferts, Ali Amr, Daniel Tian Li, Omid Shirvani Samani, Avisha Carstensen, Diana Martins Bordalo, Marion Müller, Christine Fischer, Jing Shao, Jing Wang, Ming Nie, Li Yuan, Sabine Haßfeld, Christine Schwartz, Min Zhou, Zihua Zhou, Yanwen Shu, Min Wang, Kai Huang, Qiutang Zeng, Longxian Cheng, Tobias Fehlmann, Philipp Ehlermann, Andreas Keller, Christoph Dieterich, Katrin Streckfuß-Bömeke, Yuhua Liao, Michael Gotthardt, Hugo A Katus, Benjamin Meder
Aims: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23...
December 7, 2017: European Heart Journal
Claire E Martin, Kelly A Petersen, Lamine Aoudjit, Manali Tilak, Vera Eremina, W Rod Hardy, Susan E Quaggin, Tomoko Takano, Nina Jones
Nephrin is a key structural component of the podocyte slit diaphragm, and proper expression of nephrin on the cell surface is critical to ensure integrity of the blood filtration barrier. Maintenance of nephrin within this unique cell junction has been proposed to require dynamic phosphorylation events and endocytic recycling, although the molecular mechanisms that control this interplay are poorly understood. Here, we investigated the possibility that the phosphotyrosine adaptor protein ShcA regulates nephrin turnover...
October 10, 2017: Journal of the American Society of Nephrology: JASN
Eleni Nikolakaki, Ilias Mylonis, Thomas Giannakouros
Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane, containing a hydrophilic N-terminal end protruding into the nucleoplasm, eight hydrophobic segments that span the membrane and a short, nucleoplasmic C-terminal tail. Two seemingly unrelated functions have been attributed to LBR. Its N-terminal domain tethers heterochromatin to the nuclear periphery, thus contributing to the shape of interphase nuclear architecture, while its transmembrane domains exhibit sterol reductase activity...
August 31, 2017: Cells
Alexandre Janin, Delphine Bauer, Francesca Ratti, Gilles Millat, Alexandre Méjat
Since the identification of the first disease causing mutation in the gene coding for emerin, a transmembrane protein of the inner nuclear membrane, hundreds of mutations and variants have been found in genes encoding for nuclear envelope components. These proteins can be part of the inner nuclear membrane (INM), such as emerin or SUN proteins, outer nuclear membrane (ONM), such as Nesprins, or the nuclear lamina, such as lamins A and C. However, they physically interact with each other to insure the nuclear envelope integrity and mediate the interactions of the nuclear envelope with both the genome, on the inner side, and the cytoskeleton, on the outer side...
August 30, 2017: Orphanet Journal of Rare Diseases
Federica F Morelli, Dineke S Verbeek, Jessika Bertacchini, Jonathan Vinet, Laura Mediani, Sandra Marmiroli, Giovanna Cenacchi, Milena Nasi, Sara De Biasi, Jeanette F Brunsting, Jan Lammerding, Elena Pegoraro, Corrado Angelini, Rossella Tupler, Simon Alberti, Serena Carra
Small heat shock proteins (HSPBs) contain intrinsically disordered regions (IDRs), but the functions of these IDRs are still unknown. Here, we report that, in mammalian cells, HSPB2 phase separates to form nuclear compartments with liquid-like properties. We show that phase separation requires the disordered C-terminal domain of HSPB2. We further demonstrate that, in differentiating myoblasts, nuclear HSPB2 compartments sequester lamin A. Increasing the nuclear concentration of HSPB2 causes the formation of aberrant nuclear compartments that mislocalize lamin A and chromatin, with detrimental consequences for nuclear function and integrity...
August 29, 2017: Cell Reports
Alfonso Fernández-Álvarez, Julia Promisel Cooper
Despite its ubiquity in interphase eukaryotic nuclei, the functional significance of the RabI configuration, in which interphase centromeres are clustered at the nuclear envelope (NE) near the centrosome and telomeres localize at the opposite end of the nucleus, has remained mysterious. In a broad variety of organisms, including Schizosaccharomyces pombe, the RabI configuration is maintained throughout mitotic interphase. The fission yeast linker of nucleoskeleton and cytoskeleton (LINC) complex mediates this centromere association...
August 3, 2017: Cell Cycle
Cecilia Bergqvist, Mohammed Hakim Jafferali, Santhosh Gudise, Robert Markus, Einar Hallberg
The ability of iPSCs (induced pluripotent stem cells) to generate any cell type in the body makes them valuable tools for cell replacement therapies. However, differentiation of iPSCs can be demanding, slow and variable. During differentiation chromatin is re-organized and silent dense heterochromatin becomes tethered to the nuclear periphery by processes involving the nuclear lamina and proteins of the INM (inner nuclear membrane). The INM protein, Samp1 (Spindle Associated Membrane Protein 1) interacts with Lamin A/C and the INM protein Emerin, which has a chromatin binding LEM (Lap2-Emerin-Man1)-domain...
August 2017: Stem Cell Research
Michael I Robson, Jose I de Las Heras, Rafal Czapiewski, Aishwarya Sivakumar, Alastair R W Kerr, Eric C Schirmer
The 3D organization of the genome changes concomitantly with expression changes during hematopoiesis and immune activation. Studies have focused either on lamina-associated domains (LADs) or on topologically associated domains (TADs), defined by preferential local chromatin interactions, and chromosome compartments, defined as higher-order interactions between TADs sharing functionally similar states. However, few studies have investigated how these affect one another. To address this, we mapped LADs using Lamin B1-DamID during Jurkat T-cell activation, finding significant genome reorganization at the nuclear periphery dominated by release of loci frequently important for T-cell function...
July 2017: Genome Research
Lamine Traore, Yannick Kergosien, Daniel Racoceanu
With the wider acceptance of Whole Slide Images (WSI) in histopathology domain, automatic image analysis algorithms represent a very promising solution to support pathologist's laborious tasks during the diagnosis process, to create a quantification-based second opinion and to enhance inter-observer agreement. In this context, reference vocabularies and formalization of the associated knowledge are especially needed to annotate histopathology images with labels complying with semantic standards. In this work, we elaborate a sustainable triptych able to bridge the gap between pathologists and image analysis scientists...
2017: Studies in Health Technology and Informatics
Can Zhou, Chen Li, Bin Zhou, Huaqin Sun, Victoria Koullourou, Ian Holt, Megan J Puckelwartz, Derek T Warren, Robert Hayward, Ziyuan Lin, Lin Zhang, Glenn E Morris, Elizabeth M McNally, Sue Shackleton, Li Rao, Catherine M Shanahan, Qiuping Zhang
Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening...
June 15, 2017: Human Molecular Genetics
Annie Laquerriere, Camille Maillard, Mara Cavallin, Françoise Chapon, Florent Marguet, Arnaud Molin, Sabine Sigaudy, Marie Blouet, Guillaume Benoist, Carla Fernandez, Karine Poirier, Jamel Chelly, Sophie Thomas, Nadia Bahi-Buisson
Dyneins play a critical role in a wide variety of cellular functions such as the movement of organelles and numerous aspects of mitosis, making it central player in neocortical neurogenesis and migration. Recently, cytoplasmic dynein-1, heavy chain-1 (DYNC1H1) mutations have been found to cause a wide spectrum of brain cortical malformations. We report on the detailed neuropathological features of brain lesions from 2 fetuses aged 36 and 22 weeks of gestation (WG), respectively, carrying de novo DYNC1H1 mutations, p...
March 1, 2017: Journal of Neuropathology and Experimental Neurology
Xiuli Bi, Ying-Juan Cheng, Bo Hu, Xiaoli Ma, Rui Wu, Jia-Wei Wang, Chang Liu
The nuclear space is not a homogeneous biochemical environment. Many studies have demonstrated that the transcriptional activity of a gene is linked to its positioning within the nuclear space. Following the discovery of lamin-associated domains (LADs), which are transcriptionally repressed chromatin regions, the nonrandom positioning of chromatin at the nuclear periphery and its biological relevance have been studied extensively in animals. However, it remains unknown whether comparable chromatin organizations exist in plants...
July 2017: Genome Research
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