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• W2017207046 abstract "Lamin mutations cause muscular dystrophies, but the mechanism is unclear. A new study shows that lamin mutant worms display muscle-specific defects linked to altered subnuclear localization of heterochromatin, leading to altered gene expression. Lamin mutations cause muscular dystrophies, but the mechanism is unclear. A new study shows that lamin mutant worms display muscle-specific defects linked to altered subnuclear localization of heterochromatin, leading to altered gene expression. The nuclear lamina is a fibrous network of proteins associated with the inner nuclear envelope. The primary structural components of this network are the nuclear lamins, intermediate filament proteins that form a very stable filamentous meshwork [1Dechat T. Adam S.A. Taimen P. Shimi T. Goldman R.D. Nuclear lamins. Cold Spring Harb.Perspect. Biol. 2010; 2: a000547Google Scholar]. The lamina both protects the nucleus from physical stresses and plays a crucial role in the spatial organization of chromatin. Most heterochromatin is localized at the nuclear periphery and large portions of the genome in worms, flies and mammals contact the nuclear lamina. Such Lamin-Associated Domains (LADs) are gene-poor, poorly expressed and enriched for heterochromatic chromatin modifications [2Guelen L. Pagie L. Brasset E. Meuleman W. Faza M.B. Talhout W. Eussen B.H. de Klein A. Wessels L. de Laat W. et al.Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions.Nature. 2008; 453: 948-951Crossref PubMed Scopus (1213) Google Scholar]. As genes are induced during differentiation, they dissociate from the lamina and move from the nuclear periphery to a more internal location [3Peric-Hupkes D. Meuleman W. Pagie L. Bruggeman S.W. Solovei I. Brugman W. Gräf S. Flicek P. Kerkhoven R.M. van Lohuizen M. et al.Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.Mol. Cell. 2010; 38: 603-613Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 4Kosak S.T. Skok J.A. Medina K.L. Riblet R. Le Beau M.M. Fisher A.G. Singh H. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development.Science. 2002; 296: 158-162Crossref PubMed Scopus (566) Google Scholar]. Therefore, the interaction of chromatin with the nuclear lamina has been suggested to promote silencing and heterochromatin formation. Consistent with this idea, the transcription of many genes is repressed by artificially tethering to the lamina [5Reddy K.L. Zullo J.M. Bertolino E. Singh H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina.Nature. 2008; 452: 243-247Crossref PubMed Scopus (546) Google Scholar, 6Finlan L.E. Sproul D. Thomson I. Boyle S. Kerr E. Perry P. Ylstra B. Chubb J.R. Bickmore W.A. Recruitment to the nuclear periphery can alter expression of genes in human cells.PLoS Genet. 2008; 4: e1000039Crossref PubMed Scopus (409) Google Scholar]. Mutations in lamins and lamin-associated proteins lead to many human diseases known collectively as ‘laminopathies’ [7Worman H.J. Ostlund C. Wang Y. Diseases of the nuclear envelope. Cold Spring Harb.Perspect. Biol. 2010; 2: a000760Google Scholar, 8Ostlund C. Worman H.J. Nuclear envelope proteins and neuromuscular diseases.Muscle Nerve. 2003; 27: 393-406Crossref PubMed Scopus (79) Google Scholar]. These include several muscular dystrophies and myopathies. For example, Emery Dreifuss Muscular Dystophy (EDMD) is caused by mutations in both lamin A/C and a lamin-binding protein and primarily affects skeletal and cardiac muscle. Two models have been proposed to explain the specific degeneration of muscle tissues in these diseases. One model suggests that muscle tissues are subject to extreme mechanical stresses, making them very sensitive to lamin dysfunction. The death of these cells would therefore be a result of DNA damage due to mechanical abuse. An alternative model proposes that muscle defects are due to defective nuclear organization of chromatin, leading to altered gene expression. Whereas the first model provides an explanation for the tissue-specificity, the second does not. A new paper from the labs of Susan Gasser and Yosef Gruenbaum [9Mattout A. Pike B.L. Towbin B.D. Bank E.M. Gonzalez A. Stadler M.B. Meister P. Gruenbaum Y. Gasser S.M. An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.Curr. Biol. 2011; 21: 1603-1614Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar] published in this issue of Current Biology provides important new insight into the molecular basis of EDMD. The authors have developed the roundworm Caenorhabditis elegans as a model for the disease. Worms possess only a single lamin gene (in which mutants exist), are readily transformed and are famously amenable to RNAi knockdown. The authors sought to explore how either loss of lamin function or a dominant EDMD mutant allele of lamin (equivalent to a Y45C substitution in the human Lamin A/C gene; Y59C in worms) affected the localization and expression of genes embedded in heterochromatin. To address these questions, they utilized a system that the Gasser lab has developed to localize arrays of integrated plasmids in living animals [10Meister P. Towbin B.D. Pike B.L. Ponti A. Gasser S.M. The spatial dynamics of tissue-specific promoters during C. elegans development.Genes Dev. 2010; 24: 766-782Crossref PubMed Scopus (151) Google Scholar]. Plasmids integrate into the worm genome in arrays of hundreds of copies. The plasmids used in this study express the GFP–lac repressor and possess a lac repressor binding site, allowing localization. They also possess an RFP reporter driven from different tissue-specific promoters. The localization of these arrays reflects both their size and the activity of the promoters [10Meister P. Towbin B.D. Pike B.L. Ponti A. Gasser S.M. The spatial dynamics of tissue-specific promoters during C. elegans development.Genes Dev. 2010; 24: 766-782Crossref PubMed Scopus (151) Google Scholar]. Large arrays localize at the nuclear periphery in tissues in which they are not expressed but localize to a more internal site in tissues in which they are expressed (Figure 1). Using this powerful tool, the authors asked how altering the lamina affects the localization and expression of these plasmids. If laminopathies like EDMD were caused by loss of lamin function through either depletion or dominant negative effects, loss of lamin and expression of the Y59C lamin should have similar phenotypes. However, a null mutant in worm lamin and expression of the EDMD mutant form of lamin had opposite effects [9Mattout A. Pike B.L. Towbin B.D. Bank E.M. Gonzalez A. Stadler M.B. Meister P. Gruenbaum Y. Gasser S.M. An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.Curr. Biol. 2011; 21: 1603-1614Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Whereas lamin depletion led to loss of peripheral localization and over-expression of the reporter gene, expression of Y59C lamin caused inappropriate retention of the plasmid array at the nuclear periphery and poor expression of the muscle reporter (Figure 1). These effects were muscle-specific; in the muscle cells of the animals expressing Y59C lamin, a reporter plasmid array having a muscle-specific promoter was retained at the nuclear periphery and its expression was reduced. However, in gut cells, a reporter plasmid array bearing a gut-specific promoter moved from the nuclear periphery to the nuclear interior normally. This suggests that Y59C is a gain-of-function mutation that blocks relocalization of facultative heterochromatin in a tissue-specific fashion. In addition to the effects on the localization and expression of transgenic arrays of plasmids, expression of the EDMD form of lamin led to defects in muscle function and morphology. Expression of Y59C significantly reduced the frequency of the back and forth movement of the animals' heads during swimming. This effect was abrogated when the animals were treated with RNAi against the Y59C lamin, indicating that it was a product of the dominant mutant. Furthermore, the Y59C-expressing animals exhibited disorganized actin fibers and sarcomeres in muscle cells. Thus, expression of Y59C lamin affects both nuclear organization of chromatin and muscle cell function, suggesting that the worm system may be a good model for the human pathology. What is the connection between defective movement of heterochromatin from the nuclear periphery to the nucleoplasm and the muscle-specific defects? The authors note that many genes that are important for muscle biogenesis are located near the ends of chromosomes, within LADs [11Ikegami K. Egelhofer T.A. Strome S. Lieb J.D. Caenorhabditis elegans chromosome arms are anchored to the nuclear membrane via discontinuous association with LEM-2.Genome Biol. 2010; 11: R120Crossref PubMed Scopus (127) Google Scholar], and that several of these genes are poorly expressed in Y59C animals. This suggests a model for the muscle-specific effects: if muscle cell biology is more sensitive to expression of genes embedded in LADs than other tissues, they might be more sensitive to gain-of-function mutants like Y59C. It remains to be seen if these genes are actually retained at the nuclear periphery and if this is the cause of their poor expression. This worm model for EDMD has raised many interesting questions that will be addressed in future work. Why is the localization and expression of facultative heterochromatin altered in muscle, but not in gut? Is the localization and expression of muscle-specific genes altered in EDMD patients? Finally, how does the phenotype of the Y59C EDMD mutation relate to the phenotypes of other laminopathies, some of which are recessive or have very different phenotypes [7Worman H.J. Ostlund C. Wang Y. Diseases of the nuclear envelope. Cold Spring Harb.Perspect. Biol. 2010; 2: a000760Google Scholar]? An EDMD Mutation in C. elegans Lamin Blocks Muscle-Specific Gene Relocation and Compromises Muscle IntegrityMattout et al.Current BiologySeptember 29, 2011In BriefIn worms, as in other organisms, many tissue-specific promoters are sequestered at the nuclear periphery when repressed and shift inward when activated. It has remained unresolved, however, whether the association of facultative heterochromatin with the nuclear periphery, or its release, has functional relevance for cell or tissue integrity. Full-Text PDF Open Archive" @default.
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• W2017207046 title "Nuclear Architecture: The Cell Biology of a Laminopathy" @default.
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