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

Michele M Nava1, Yekaterina A Miroshnikova1, Leah C Biggs2, Daniel B Whitefield3, Franziska Metge4, Jorge Boucas4, Helena Vihinen5, Eija Jokitalo5, Xinping Li4, Juan Manuel García Arcos6, Bernd Hoffmann7, Rudolf Merkel7, Carien M Niessen8, Kris Noel Dahl9, Sara A Wickström10

  1. 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.
  2. 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.
  3. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
  4. Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
  5. Electron Microscopy Unit, Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
  6. Institut Curie, PSL Research University, CNRS, UMR 144 and Institut Pierre-Gilles de Gennes, PSL Research University, 75005 Paris, France.
  7. Forschungszentrum Jülich, Institute of Biological Information Processing-2: Mechanobiology, 52428 Jülich, Germany.
  8. Cologne Excellence Cluster for Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Department of Dermatology, Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany.
  9. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
  10. 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: sara.wickstrom@helsinki.fi.

Abstract

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.

Presented By Yekaterina A Miroshnikova

Genomics, Cell & Developmental BioNicholas Liao2020-05 (May)