An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity

Curr Biol. 2011 Oct 11;21(19):1603-14. doi: 10.1016/j.cub.2011.08.030. Epub 2011 Sep 29.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Disease Models, Animal
  • Heterochromatin / metabolism
  • Humans
  • Laminin / genetics
  • Laminin / metabolism*
  • Locomotion
  • Microscopy
  • Muscle Development
  • Muscles / embryology
  • Muscular Dystrophy, Emery-Dreifuss / genetics*
  • Muscular Dystrophy, Emery-Dreifuss / physiopathology
  • Nuclear Envelope / metabolism
  • Point Mutation*
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Caenorhabditis elegans Proteins
  • Heterochromatin
  • LMN-1 protein, C elegans
  • Laminin
  • Pha-4 protein, C elegans
  • Trans-Activators