Emerin self-assembly and nucleoskeletal coupling regulate nuclear envelope mechanics against stress

Abstract

X-linked Emery-Dreifuss muscular dystrophy (EDMD) results from mutations of the nuclear envelope protein emerin, which participates in nuclear mechanotransductions and maintenance of nuclear shape. To better understand the molecular determinants of EDMD, we probed the membrane diffusion and the nanoscale spatial organization of emerin and some of its clinically relevant mutations, using single molecule tracking and super-resolution microscopy. We show that emerin is distributed as monomers and oligomeric clusters at the inner nuclear membrane and that both its diffusion and its oligomeric state are modified by EDMD-associated mutations. Emerin interactions with lamin A/C, nuclear actin and BAF modulate its mobility and its membrane organization. Measurements in nuclei under stress further indicate that the mechanotransducing function of emerin are coupled to its oligomeric state and that defective formation of emerin oligomers result in aberrant nuclear deformation against forces. These findings place emerin at the center of the molecular processes that regulate nuclear shape remodeling in response to mechanical stress.

The LINC complex inhibits excessive chromatin repression

“…Experimentally we show that chromatin distribution indeed shifts from the nuclear periphery towards the nuclear center in the SUN/koi mutant nuclei, implicating weakening of chromatin -nuclear lamina binding. Consistently, recent studies indicated that in LINC mutants the LEM domain protein Emerin, which together with BAF promotes chromatin tethering to the lamina, fails to oligomerize at the inner nuclear membrane (Fernandez et al, 2022), and consistently BAF is eliminated from the nuclear envelope (Unnikannan et al, 2020); both evidence predict chromatin dissociation from the nuclear envelope in the LINC mutants as was observed.…”

The BAF A12T mutation associated with premature aging impedes lamin A/C recruitment to sites of nuclear rupture, contributing to nuclear envelope fragility

“…For example, it could explain why the A12T mutation causes delocalization of emerin from the NE to the cytoplasm in NGPS cells, even though the mutation is not expected to impair BAF-emerin binding directly. Both BAF and lamin are important for the nuclear enrichment and dynamics of emerin (Haraguchi et al , 2008; Fernandez et al , 2022). Therefore, inefficient immobilization of emerin in BAF-emerin-lamin A/C tertiary complexes at the NE caused by the reduced binding of BAF to lamin A/C could affect emerin nuclear localization.…”

The role of physical cues in the development of stem cell-derived organoids

“…For example, matrix elasticity regulates the differentiation of Mesenchymal Stem Cells (MSCs) with the general concept that rigidity is associated with chondrogenic/osteogenic lineages and softer matrices induce neuronal or fat differentiation (Engler et al 2006;Huebsch et al 2010;Khetan et al 2013;Vining and Mooney 2017;Romani et al 2021). (Willer and Carroll 2017;Fernandez et al 2021) Indeed, stiffness is a decisive parameter for mimicking the stem cells' niche and it can be tuned using synthetic matrices which, in this way, offer the possibility of investigating its effect on organoids formation (Gjorevski et al 2016). About this, new mechanical refined materials such as complex hydrogels with tunable architecture and composition that offer the possibility of precisely control the orientation of functional groups showed that the regulation of matrix viscoelasticity and gel degradability is of particular importance for a successful organoid formation and culture (Cruz-Acuña et al 2017;Chaudhuri et al 2020).…”