Mechanism and function of genome organization in muscle development and integrity
Prof. Susan Gasser, Friederich Miescher Institute, BAsel
Abstract (Lay summary see below)
Laminopathies are a set of diseases that manifest in specific tissues, with muscle being most commonly affected. While rare, these conditions have phenotypes that could provide insight into more common disorders, including muscular dystrophies, insulin resistance and aging. Despite their varied symptoms, laminopathies have in common the fact that one protein, lamin A, or proteins that interact with lamin A, are mutated. The nuclear lamina collectively ensures the shape of the nucleus and influences the distribution of genomic domains bearing specific heterochromatic marks. In most differentiated metazoan cells, the condensed, transcriptionally silent fraction of the genome called heterochromatin is found at the nuclear rim. It is tethered there apparently through the interaction of chromatin factors with nuclear lamina components. Our research proposal is based on the hypothesis that cell-type specific chromatin organization maintains cell-type integrity, and that its perturbation can result in a degenerative condition, such as muscular dystrophy. We propose to use the nematode C. elegans to further examine the impact of chromatin organization on the integrity of striated muscle function. In a previous study, we have shown that introduction of an Emery-Dreifuss Muscular Dystrophy (EDMD)-like mutation in the C. elegans lamin gene impaired the release of a muscle-specific transgene reporter from the nuclear periphery. This release normally occurs during muscle differentiation. The gain-of-function phenotype linked to the lamin mutation impaired worm movement and altered body wall muscle ultrastructure. We now show that the deletion of a novel perinuclear C. elegans chromodomain protein (CEC-4), which anchors heterochromatin through the binding of histone H3K9 methylation, reversed many of these defects (A. Mattout, A Gonzalez-Sandoval, et al., unpublished). This argues that the lamin-induced sequestration or retention of tissue specific genes in a heterochromatic compartment drives defects that can be suppressed by reversing perinuclear sequestration. Since the deletion of CEC-4 does not confer gross defects on muscle development, this process merits further study as a potential therapeutic approach. We will take an in vivo biochemical approach to identify the components of the nuclear lamina that sequester muscle-specific genes and those that lead to their release. Following up on a preliminary drug screen that we have performed in whole worms, we will identify compounds that can alter heterochromatin organization without globally affecting gene expression. We will determine the stage of development at which phenotype reversal is possible. This has direct implications for understanding how lamin-induced mis-organization of the genome influences muscle integrity, a topic relevant for muscular dystrophies and other degenerative diseases.
Lay summary
Les effets de l’organisation du génome dans le noyau sur le développement musculaire
Les laminopathies sont un ensemble de maladies génétiques qui affectent particulièrement un tissu, celui-ci étant très souvent le tissu musculaire. Bien que ces maladies soient rares, leur étude est susceptible d’apporter aussi une compréhension plus générale sur les dystrophies musculaires, les effets de l’insuline et le vieillissement. Malgré la diversité des symptômes, les laminopathies ont en commun le fait qu’une protéine, la lamine A, ou une autre protéine interagissant avec la lamine A, contienne une mutation. Ce réseau de protéines associées aux lamines, aussi appelé la lamine nucléaire, assure la forme correcte du noyau et influence la localisation des régions hétérochromatiques du génome à la périphérie du noyau. L’ hétérochromatine est la partie du génome transcriptionellement inactive (ne produisant pas de protéines). Dans la plupart des cellules animales, l’hétérochromatine se trouve ancrée à la périphérie nucléaire grâce aux interactions entre certaines protéines de la chromatine et de la lamine nucléaire.
Notre proposition de recherche est basée sur l’hypothèse qu’une distribution spécifique de la chromatine et de l’hétérochromatine dans le noyau est importante pour le maintien des cellules dans un statut de différenciation donné (cellules musculaires, cellules nerveuses etc.). Aussi, cela implique qu’une perturbation de l’organisation du génome pourrait engendrer une dégénération des tissus, comme la dystrophie musculaire. Nous proposons d’utiliser le ver microscopique, C. elegans, pour examiner l’impact de l’organisation du génome sur le fonctionnement des cellules musculaires striées. Ces cellules sont très similaires chez l’homme et C. elegans dans leur fonctionnement de base. Lors d’une recherche antérieure, nous avons montré que quand une des mutations causant la Dystrophie Musculaire Emery-Dreifuss (EDMD) chez l’homme était introduite dans le gène de lamine de C. elegans, cela provoquait une rétention à la périphérie du noyau de certaines régions du génome qui ne devraient pas l’être dans les cellules musculaires. Cette organisation incorrecte de certaines parties du génome corrélait avec une mobilité réduite de ces animaux, ainsi qu’avec une structure altérée de leurs cellules musculaires (Mattout et al., 2011). Récemment, nous avons de surcroît observé que la suppression de la protéine CEC-4, pouvait inverser ces observations et rétablir une mobilité normale (Mattout, communication personnelle). CEC-4 est une protéine qui a été identifiée dernièrement et est essentielle pour l’ancrage de l’hétérochromatine à la périphérie nucléaire (Gonzalez-Sandoval et al., 2015). Tous ces éléments montrent que l’organisation incorrecte du génome, avec la rétention de certaines régions à la périphérie du noyau due à une mutation dans la lamine cause des défauts physiologiques qui peuvent être annulés en modifiant la localisation périnucléaire de l’hétérochromatine.
Puisque la suppression de CEC-4 ne confère pas d’anomalies majeures sur le développement musculaire, cette direction de recherche mérite d’être poursuivie pour une approche thérapeutique potentielle. Nous essaierons d’identifier de nouveaux composants de la lamine nucléaire qui pourraient séquestrer à la périphérie ou relâcher des gènes importants pour le fonctionnement musculaire. Nous poursuivrons également une série d’expériences en testant une collection de substances chimiques susceptibles de rétablir la mobilité des animaux porteurs la mutation EDMD en identifiant les substances pouvant rétablir une organisation normale du génome. Ceci aidera à mieux comprendre comment l’organisation incorrecte du génome due à une mutation dans la lamine influence l’intégrité musculaire, un sujet pertinent pour les dystrophies musculaires et pour d’autres maladies dégénératives.
Projekte
- Neue Forschungsprojekte ab 2024
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