Nuclear envelope mechanics and genome tethering in gene regulation: constrained diffusion and the lamin spring
The nuclear envelope (NE) is a complex double membrane system supported by the intermediate filament lamin polymer and many NE transmembrane proteins (NETs) that connect it to both cytoplasmic filaments from the outer nuclear membrane and chromatin from the inner nuclear membrane. These latter connections play a major role in 3D spatial genome organization that provides an additional layer of complexity to gene regulation. We have identified several tissue-specific nuclear envelope transmembrane proteins (NETs) from muscle, fat, liver and blood that are each important for establishing genome organization patterns in their respective tissues. Each affects the positioning and expression of distinct sets of important genes for tissue functioning and/or differentiation and their disruption can lead to pathologies matching those of nuclear envelope linked human disease. In addition to direct recruitment of genes to the NE, more distal tethers may constrain the diffusion of internal genome regions to facilitate the interactions of superenhancers many megabases away with genes similarly constrained. I will also address some aspects of the mechanics of the lamin polymer involved in this genome tethering function and how electrostatic interactions appear to fold the ends of coiled coils on top of one another to contract the polymer into an effective 'spring' that may give the NE greater flexibility to withstand genomic and cytoskeletal forces.
The Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, and Centre for Translational and Chemical Biology - University of Edinburgh,
Domain 4 - UMR 168 - Physical chemistry