Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery Dreifuss Muscular Dystrophy (EDMD)-inducing mutation (lamin A-Y45C) into lamin (LMN-Y59C) in worms, recapitulates many EDMD phenotypes, and correlates with hyper-sequestration of heterochromatic arrays at the nuclear periphery. Using muscle-specific emerin Dam-ID, we document the misorganization of endogenous chromatin in the LMN-Y59C mutant. We score increased perinuclear positioning along chromosome arms, and enhanced release of chromosomal centers, which accompany the disease phenotypes of reduced locomotion and compromised sarcomere integrity. By coupling the Y59C mutation with deletion of the perinuclear chromodomain protein CEC-4, which tethers H3K9-methylated chromatin, we rescue the EDMD-like physiology and ultrastructural defects in sarcomeres. Deletion of cec-4 also rescued the Y59C-induced changes in chromatin organization. Gene expression changes provoked by LMN-Y59C are also largely reversed by cec-4 deletion. The promoters of genes that change position in the LMNY59C mutant, are enriched for E2F (EFL-1/-2) binding sites, consistent with previous studies implicating the Rb-E2F interaction with lamin A in muscle dysfunction. In summary, the ablation of a perinuclear H3K9me-anchor can counteract the dominant muscle-specific defects provoked by a laminopathic mutation, implicating peripheral chromatin organization in the control of muscle integrity.
The manuscript reporting our findings has been submitted and reviewed. It is currently in revision at the journal Genes and Development. The publication of this work at a major scientific journal will be its primary mode of dissemination. It has also been presented at multiple international conferences.
