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Abstract Cells perceive and relay external mechanical forces into the nucleus through the nuclear envelope. Here we examined the effect of lowering substrate stiffness as a paradigm to address the impact of altered mechanical forces on nuclear structure-function relationships. RNA sequencing of cells on softer matrices revealed significant transcriptional imbalances, predominantly in chromatin associated processes and transcriptional deregulation of human Chromosome 1. Furthermore, 3-Dimensional fluorescence in situ hybridization (3D-FISH) analyses showed a significant mislocalization of Chromosome 1 and 19 Territories (CT) into the nuclear interior, consistent with their transcriptional deregulation. However, CT18 with relatively lower transcriptional dysregulation, also mislocalized into the nuclear interior. Furthermore, nuclear Lamins that regulate chromosome positioning, were mislocalized into the nuclear interior in response to lowered matrix stiffness.

Notably, Lamin B2 overexpression retained CT18 near the nuclear periphery in cells on softer matrices. While, cells on softer matrices also activated emerin phosphorylation at a novel Tyr99 residue, the inhibition of which in a phospho-deficient mutant (emerinY99F), selectively retained chromosome 18 and 19 but not chromosome 1 territories at their conserved nuclear locations. Taken together, emerin functions as a key mechanosensor, that modulates the spatial organization of chromosome territories in the interphase nucleus. INTRODUCTION The cytoskeleton perceives and relays altered extracellular forces into the nucleus in order to regulate growth, development and differentiation (). The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex communicates extracellular forces into the nucleus via cytoskeletal proteins on the cytoplasmic side and lamins at the inner nuclear membrane. Lamins transduce external mechanical signals into the genome to elicit appropriate mechanosensitive gene expression signatures and transcriptional responses ().

The nuclear lamina is a ‘molecular shock absorber’ that maintains nuclear morphology to counter extraneous mechanical tension, while lamin associated nuclear envelope proteins namely, emerin, LAP2β and MAN1 (LEM Domain proteins) regulate mechanotransduction into the nucleus (). Interestingly, extracellular substrate stiffness modulates expression levels and phosphorylation of Lamin A ().

In addition, emerin is a mechanosensor that directly interacts with Lamin A/C and is phosphorylated in response to increased mechanical stress (). Tomabo mp4 downloader pro license key. It is well established that the genome is non-randomly organized in the interphase nucleus, with gene rich chromosome territories toward the nuclear interior, while gene poor chromosome territories are proximal to the nuclear periphery (). However, this otherwise conserved chromosome organization is altered during differentiation, senescence, quiescence, in serum starved cells or in cells treated with DNA damaging agents, within minutes to hours ().