Mechanical-stress induced DNA damage and genome mechanoprotection in cellular and organismal homeostasis

While executing their functions, tissues and single cells are exposed to specific mechanical forces such as compression, shear, tensile stress, or hydrostatic pressure. Recent evidence from us and others points to the nucleus as a mechanosensor that senses its own deformation in response to force to trigger mechanosignaling. Importantly, nuclear deformation is also associated with DNA damage, but the precise mechanisms and functional consequences to tissue and organismal homeostasis remain unclear.

Intriguingly, it was recently demonstrated that living Caenorhabditis elegans nematodes respond to extrinsic mechanical loading with nuclear deformation similar to cultured mammalian cells. Thus, together with the well-understood and conserved DNA repair mechanisms, C. elegans provides an excellent model to probe mechanisms and consequences of genome mechanoprotection and mechanical stress-induced DNA damage in vivo and on the organismal scale. We propose a multidisciplinary project of cell mechanobiology and C. elegans genetics to tackle the molecular mechanisms and physiological consequences of force-induced DNA damage. Combining cutting edge sequencing, imaging, and mechanical manipulation approaches in mammalian induced pluripotent stem cells with in vivo studies in the C. elegans stem cell compartment, the germline, we will decipher evolutionarily conserved mechanisms and organismal consequences of stem cell genome responses to nuclear shape/volume changes and study how chromatin rearrangements and transcriptional/replication alterations impact genome integrity.

PROJECT RELATED PUBLICATIONS

Bertillot F, Miroshnikova YA, Wickström SA. (2022) SnapShot: Mechanotransduction in the nucleus. Cell 185, 3638-3638.
Dupont S, Wickström SA. (2022) Mechanical regulation of chromatin and transcription. Nat Rev Genet. May 23. doi: 10.1038/s41576-022-00493-6
Koester J, Miroshnikova YA, Ghatak S, Chacón-Martínez CA, Morgner J, Li X, Atanassov I, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, Wickström SA. (2021) Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters. Nat Cell Biol 7:771-781.
Miroshnikova YA, Wickström SA (2021) Mechanical forces in nuclear organization. Cold Spring Harb Perspect Biol. Cold Spring Harb Perspect Biol. June 29. pii: a039685
Maki K, Nava MM, Villeneuve C, Chang M, Furukawa KS, Ushida T, Wickström SA. (2021) Hydrostatic pressure promotes chondrocyte quiescence and progenitor state through heterochromatin remodeling and suppression of replicative stress. J Cell Sci 134(2):jcs247643
Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, Vihinen H, Jokitalo E, Li X, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Dahl KN, Wickström SA. (2020) Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage Cell 181, 800-817 Highlighted by Cell Preview, Faculty of 1000
Ou HL, Kim CS, Uszkoreit S, Wickström SA, Schumacher B (2019) Somatic Niche Cells Regulate the CEP-1/p53-Mediated DNA Damage Response in Primordial Germ Cells Dev Cell 50, 167-183
Le HQ, Ghatak S, Yeung CY, Tellkamp F, Günschmann C, Dieterich C, Yeroslaviz A, Habermann B, Pombo A, Niessen CM, Wickström SA. (2016). Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat Cell Biol. 18, 864-875. Highlighted by Nature Reviews Molecular Cell Biology, Faculty of 1000