Role of nuclear lamins as integrators of extranuclear signals and regulators of genome organization and function

Abstract

The nuclear envelope and its associated proteins integrate different types of intra and extracellular signals perceived by the cell and relay them into the nucleus to elicit signal specific transcriptional responses The nuclear envelope maintains structure mechano responsiveness and plasticity of the nucleus via the Linker of Nucleoskeleton and Cytoskeleton LINC complex nuclear Lamins and mechanosensitive proteins such as Emerin that interacts with Lamin A C A structurally and functionally pliable nucleus modulates genome organization and function across cellular processes Studying the role of nuclear envelope proteins as responders and effectors of extranuclear signals is essential to understand the regulation of mechanical and biochemical signal transduction into the nucleus Here we examined the impact of two different signaling paradigms 8211 i perception of altered extracellular substrate stiffness and ii heat shock response on nuclear structure function relationships in diploid DLD 1 cells and their regulation by nuclear envelope proteins like Lamins and Emerin RNA sequencing and 3 Dimensional fluorescence in situ hybridization 3D FISH analyses in DLD 1 cells on softer polyacrylamide matrices revealed mislocalization of transcriptionally deregulated chromosomes 8211 Chr 1 and 19 as well as Chr 18 with least transcriptional changes towards the nuclear interior Furthermore nuclear Lamins which modulate chromosome positioning were also mislocalized into the nuclear interior in these cells We identified a novel phosphorylation of Emerin at Tyr99 in cells on softer matrices the inhibition of which in a phospho deficient mutant emerinY99F selectively retained chromosome territories as well as Lamins at their conserved nuclear locations Taken together Emerin functions as a key mechanosensor that selectively modulates the spatial organization of chromosome territories in the interphase nucleus in a Lamin dependent manner Interestingly we observed that Lamin A and B1 were upregulated during heat shock res