Abstract
BackgroundLaminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. While most nuclear envelope proteins are ubiquitously expressed, laminopathies often affect only a subset of tissues. The molecular mechanisms underlying these tissue-specific manifestations remain elusive. We hypothesize that different functional subclasses of genes might be differentially affected by defects in specific nuclear envelope components.ResultsHere we determine genome-wide DNA association profiles of two nuclear envelope components, lamin/LMN-1 and emerin/EMR-1 in adult Caenorhabditis elegans. Although both proteins bind to transcriptionally inactive regions of the genome, EMR-1 is enriched at genes involved in muscle and neuronal function. Deletion of either EMR-1 or LEM-2, another integral envelope protein, causes local changes in nuclear architecture as evidenced by altered association between DNA and LMN-1. Transcriptome analyses reveal that EMR-1 and LEM-2 are associated with gene repression, particularly of genes implicated in muscle and nervous system function. We demonstrate that emr-1, but not lem-2, mutants are sensitive to the cholinesterase inhibitor aldicarb, indicating altered activity at neuromuscular junctions.ConclusionsWe identify a class of elements that bind EMR-1 but do not associate with LMN-1, and these are enriched for muscle and neuronal genes. Our data support a redundant function of EMR-1 and LEM-2 in chromatin anchoring to the nuclear envelope and gene repression. We demonstrate a specific role of EMR-1 in neuromuscular junction activity that may contribute to Emery-Dreifuss muscular dystrophy in humans.
Highlights
Laminopathies are diseases characterized by defects in nuclear envelope structure
Identification of chromatin anchored to LMN-1 and EMR-1 by DNA adenine methyltransferase identification (DamID) To investigate the specific role that different components of the nuclear envelope (NE) play in the control of chromatin organization and gene expression, we generated genome-wide interaction maps of the sole C. elegans nuclear lamina protein, lamin/LMN-1, and the inner nuclear membrane protein emerin/EMR-1, in adult C. elegans nematodes using
A comparison of the genome-wide DNA association profiles of LMN-1, the only lamin protein in C. elegans, and of the inner nuclear membrane (INM) protein emerin/EMR-1 indicates that EMR-1 defines two types of chromatin domains: a major type consisting of LMN-1-associated domain (LAD) and a minor type devoid of LMN-1 and enriched for genes expressed in specific tissues
Summary
Laminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. The NE is an important player in a number of cellular functions, including maintenance of structural integrity of the nucleus, chromatin organization, transcriptional regulation, DNA replication, cell-cycle control, differentiation, nuclear migration, and apoptosis [1,3,4,5] Reflecting these many functions, mutations in NE components have been associated with numerous human diseases. One proposed hypothesis argues that an alteration of the integrity of the NE - for example, by affecting the nuclear lamina or the connection of the NE with the cytoskeleton - could lead to a structural weakness and a decrease in the ability of the nucleus to resist mechanical stress [10,11,12] This could be of special relevance in muscle and skeletal disorders. The nuclear lamins interact with chromatin remodelers involved in heterochromatin formation, such as heterochromatin protein HP1 or the NURD complex [15]
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