The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity

Abstract

Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity. We show that gene mechanosensitivity is preserved after LINC disruption, but reversed in direction. Combined with myosin inhibition studies, we identify genes that depend on nuclear tension for their regulation. We also show that LINC disruption does not attenuate nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex facilitates mechano-regulation of expression across the genome.

The nucleus is irreversibly shaped by motion of cell boundaries in cancer and non‐cancer cells

“…To explain the large plastic deformations of nuclei observed by Pajerowski et al () in cells lacking lamin A/C, they modeled chromatin as a plastic material surrounded by a much softer hyperelastic shell. But, as we point out here, the nucleus in wild‐type fibroblasts—which contain normal levels of lamins (Alam et al, )—is irreversibly deformed at steady state. The assumption of the elastic nucleus has not been previously tested by removing the forces on the nuclear surface (i.e., isolating the nucleus) and then tracking its shape.…”

Centrifugal Displacement of Nuclei Reveals Multiple LINC Complex Mechanisms for Homeostatic Nuclear Positioning

“…Given these findings, and our results that active homeostatic positioning occurs in varied cellular contexts, we suggest that a constantly stressed nucleus may be a general feature of eukaryotic cells. The stressed state of the nucleus may impact functions beyond nuclear positioning, for example by activating mechanotransduction pathways inside the nucleus [47] or by altering gene expression [48]. …”

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

“…The PolyA-enriched RNA sequencing library was prepared as previously described (62). Paired-end sequencing (100 million 100-bp paired-end reads) was performed on an Illumina HiSeq2500 sequencer (Illumina Inc.).…”