LAP2β transmits force to upregulate genes via chromatin domain stretching but not compression

There is increasing evidence that force impacts almost every aspect of cells and tissues in physiology and disease including gene regulation. However, the molecular pathway of force transmission from the nu-clear lamina to the chromatin remain largely elusive. Here we employ two different approaches of a local stress on cell apical surface via an RGD (Arg-Gly-Asp)-coated magnetic bead and whole cell deformation at cell basal surface via uniaxial or biaxial deformation of a fibronectin-coated flexible polydimethyl-siloxane substrate. We find that nuclear protein LAP2 beta mediates force transmission from the nuclear lamina to the chromatin. Knocking down LAP2 beta increases spontaneous movements of the chromatin by reducing tethering of the chromatin and substantially inhibits the magnetic bead-stress or the substrate -deformation induced chromatin domain stretching and the ensuing dihydrofolate reductase (DHFR) gene upregulation. Analysis of DHFR gene-containing chromatin domain alignments along or perpendicular to the direction of the stretching/compressing reveals that the chromatin domain must be stretched and not compressed in order for the gene to be rapidly upregulated. Together these results suggest that external -load induced rapid transcription upregulation originates from chromatin domain stretching but not com-pressing and depends on the molecular force transmission pathway of LAP2 beta. Statement of significanceHow force regulates gene expression has been elusive. Here we show that the orientation of the chro-matin domain relative to the stress direction is crucial in determining if the chromatin domain will be stretched or compressed in response to a cell surface loading. We also show that nuclear protein Lap2b is a critical molecule that mediates force transmission from the nuclear laminar to the chromatin to reg-ulate gene transcription. This study reveals the molecular force transmission pathway for force-induced gene regulation.(c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

There is increasing evidence that force affects cells and tissues in various physiological and pathological processes, including gene regulation. However, the molecular pathway of force transmission from the nuclear lamina to the chromatin remains unclear. This study reveals that the nuclear protein LAP2 beta mediates force transmission from the nuclear lamina to the chromatin, and this pathway plays a crucial role in gene regulation.