Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.

Cell 2020 05 16;181(4):800-817.e22. Epub 2020 Apr 16.

Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; Cologne Excellence Cluster for Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. Electronic address:

Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.03.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237863PMC
May 2020

Publication Analysis

Top Keywords

nuclear softening
8
mechanical force
8
mechanical
7
high-amplitude stretch
4
stretch induces
4
persistent high-amplitude
4
damage persistent
4
mechanoresponse dna
4
dna damage
4
induces supracellular
4
supracellular alignment
4
redistribute mechanical
4
mechanical energy
4
tissue redistribute
4
alignment tissue
4
nuclear mechanoresponse
4
energy reaches
4
failure mount
4
heterochromatin changes
4
changes chromatin
4

Similar Publications