The loss of nuclear structural integrity leads to tissue-specific pathologies in a set of human diseases called laminopathies. These diseases, such as Emery Dreifuss Muscular Dystrophy (EDMD), are late-onset, tissue-specific, and degenerative. A C. elegans mutant that recreates the EDMD phenotypes arises from the introduction of a specific gain-of-function mutation into lamin (Y59C), which affects the proper release of a muscle-specific heterochromatic reporter from the nuclear periphery. We found that this muscle-specific misorganization of heterochromatin correlates with transcriptional defects and with perturbed locomotion and muscle integrity in C. elegans. To identify if chromatin misorganization is a cause or an effect of these physiological defects or if the alteration of gene expression is the primary cause, we took advantage of a
cec-4 deletion mutant. The perinuclear C. elegans chromodomain protein-4 (CEC-4) anchors heterochromatin by binding H3K9 methylation. The mutant releases H3K9me containing heterochromatin from the nuclear periphery in embryos and does not alter transcription. In a strain that contains the
cec-4 deletion, expresses the lamin Y59C mutant and harbors a muscle-specific heterochromatic reporter, there is a recovery of the proper positioning of the muscle-specific heterochromatic array in muscle. Additionally, we found that the
cec-4 mutation rescues the impaired locomotion phenotype of the lamin mutant. This argues that the lamin-induced sequestration or retention of tissue specific genes in a heterochromatic compartment drives defects that can be overcome by reversing perinuclear sequestration. To identify the mechanism behind this phenomenon we are using in vivo biochemical tagging in the LMN-1 Y59C mutant and wild-type counterpart to identify perinuclear components that mediate sequestration of muscle-specific gene promoters. By identifying the proteins involved in this process, we can determine the mechanism in which misorganization of chromatin can lead to a loss of tissue integrity.