title: An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.
abstract: BACKGROUND
  In 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.
  
  
  RESULTS
  Using ablation of the unique lamin gene in C. elegans, we show that lamin is necessary for the perinuclear positioning of heterochromatin. We then express at low levels in otherwise wild-type worms a lamin carrying a point mutation, Y59C, which in humans is linked to an autosomal-dominant form of Emery-Dreifuss muscular dystrophy. Using embryos and differentiated tissues, we track the subnuclear position of integrated heterochromatic arrays and their expression. In LMN-1 Y59C-expressing worms, we see abnormal retention at the nuclear envelope of a gene array bearing a muscle-specific promoter. This correlates with impaired activation of the array-borne myo-3 promoter and altered expression of a number of muscle-specific genes. However, an equivalent array carrying the intestine-specific pha-4 promoter is expressed normally and shifts inward when activated in gut cells of LMN-1 Y59C worms. Remarkably, adult LMN-1 Y59C animals have selectively perturbed body muscle ultrastructure and reduced muscle function.
  
  
  CONCLUSIONS
  Lamin helps sequester heterochromatin at the nuclear envelope, and wild-type lamin permits promoter release following tissue-specific activation. A disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction in LMN-1 Y59C worms phenocopies Emery-Dreifuss muscular dystrophy.
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Mattout
authors.forename: Brietta L
authors.initials: BL
authors.lastname: Pike
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Towbin
authors.forename: Erin M
authors.initials: EM
authors.lastname: Bank
authors.forename: Adriana
authors.initials: A
authors.lastname: Gonzalez-Sandoval
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stadler
authors.forename: Peter
authors.initials: P
authors.lastname: Meister
authors.forename: Yosef
authors.initials: Y
authors.lastname: Gruenbaum
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gasser
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion; D008853:Microscopy; D024510:Muscle Development; D009132:Muscles / Q000196:embryology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000503:physiopathology; D009685:Nuclear Envelope / Q000378:metabolism; D017354:Point Mutation; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D006570:Heterochromatin; C570326:LMN-1 protein, C elegans; D007797:Laminin; C113277:Pha-4 protein, C elegans; D015534:Trans-Activators