The nuclear lamina in health and disease

Abstract

The nuclear lamina (NL) is a structural component of the nuclear envelope and makes extensive contacts with integral nuclear membrane proteins and chromatin. These interactions are critical for many cellular processes, such as nuclear positioning, perception of mechanical stimuli from the cell surface, nuclear stability, 3-dimensional organization of chromatin and regulation of chromatin-binding proteins, including transcription factors. The NL is present in all nucleated metazoan cells but its composition and interactome differ between tissues. Most likely, this contributes to the broad spectrum of disease manifestations in humans with mutations in NL-related genes, ranging from muscle dystrophies to neurological disorders, lipodystrophies and progeria syndromes. We review here exciting novel insight into NL function at the cellular level, in particular in chromatin organization and mechanosensation. We also present recent observations on the relation between the NL and metabolism and the special relevance of the NL in muscle tissues. Finally, we discuss new therapeutic approaches to treat NL-related diseases.

Cell Biology of theCaenorhabditis elegansNucleus

“…Tension-mediated signaling from the cytoplasm is thought to have a significant impact on gene expression, both in healthy tissues and upon alteration of NE composition (Dobrzynska et al 2016). In addition to amphiphysin 2/AMPH-1 and nesprin/ ANC-1 described in the previous section, mutations in LMN-1 and EMR-1 cause muscular dystrophy.…”

“…Mutations in lamin genes, as well as genes of other NE protein such as emerin (see below), result in a variety of diseases that are collectively called laminopathies. These include Emery-Dreifuss muscular dystrophy and the premature aging syndrome Hutchison-Gilford progeria syndrome (for review see Dobrzynska et al 2016). Interestingly, although lamins are present in all tissues, different lamin mutations result in distinct tissue-specific defects.…”

“…Laminopathies are a group of diseases caused by mutations in nuclear lamina proteins (Dobrzynska et al 2016). Interestingly, many of these lamina-associated mutations affect only a subset of tissues, despite the ubiquitous expression of lamina proteins throughout the organism.…”

“…Mutation of anc-1 or unc-84 enhances the synapse formation and axon termination defects of rpm-1(+/2) and fsn-1 mutant animals, probably by altered b-catenin/BAR-1 signaling (Tulgren et al 2014). Interestingly, human emerin regulates b-catenin by sequestering it at the NE (Dobrzynska et al 2016), whereas loss of EMR-1 suppresses the axon termination phenotypes of anc-1 and anc-1; fsn-1 mutants (Tulgren et al 2014) and affects neuromuscularjunction activity (Gonzalez-Aguilera et al 2014). Further analysis will hopefully help to elucidate the mechanisms underlying these genetic interactions.…”

Plant nucleolar DNA: Green light shed on the role of Nucleolin in genome organization

“…Although the positioning of heterochromatin at the nuclear periphery is not solely dependent on the nuclear lamina, this process is crucial for genome integrity and its misregulation can provoke diseases in humans that include muscle dystrophies, neurological disorders or progeria syndromes. 3 Heterochromatin was also shown to organize in and around the nucleolus, as demonstrated by the characterization of nucleolus-associated chromatin domains (NADs) in human cells. 4,5 Several megabases of genomic DNA encompassing at least one genomic region from each of the 23 chromosomes physically associate with the nucleolus, demonstrating that NAD identity is not determined by genetic linkage to rRNA (rRNA) gene arrays located on Chr, 13, 14, 15, 21 and 22.…”