Molecular and Cellular Biology
Why you should care about nuclear mechanics and morphology - Abnormal nuclear morphology has been associated with human disease since the development of microscopes that could image the nucleus of the cell (late 1800s). Abnormal nuclear morphology has been used for nearly a century as a diagnostic marker of human diseases. An example of this is the Pap smear developed in the 1930s to diagnose cervical cancer in females. Abnormal nuclear morphology has been seen across the human disease spectrum including: aging, heart disease, muscular dystrophy, atherosclerosis, diabetes, neuronal disorders, and cancer (breast, cervical, lung, prostate, renal, leukemia). However, we still do not understand the basis for how the nucleus dictates its shape. THE SIMPLE ANSWER : Mechanics (physical strength) determines the ability to maintain shape, which dictates major nuclear functions.
Cell Nuclear Mechanics - The Stephens Lab has developed a novel micromanipulation approach to isolate and measure the force response of a single mammalian nucleus from a living cell. Using this technique, we have provided for the first time, that ability to distinguish the separate roles of the two major mechanical component of the nucleus, chromatin and lamins. Specifically, micromanipulation force measurements provide the observation of a two-regime force response dictated by chromatin for short strains and lamin A at long strains via strain stiffening (Stephens et al., 2017 MBoC). This work revealing novel findings of the separate roles of chromatin and lamins in nuclear mechanics and the critical contribution of our complementary force measurement technique is summarized in a mini-review (Stephens et al., Nucleus 2017).
Cell Nuclear Morphology - The mechanical contribution of chromatin also affects nuclear shape/morphology as decreased/increased chromatin-based nuclear mechanics induces/rescues nuclear blebbing, respectively, independent of lamin levels (Stephens et al., 2018 MBoC). Abnormal nuclear morphology results in nuclear ruptures that cause cellular dysfunction, including DNA damage, altered transcription, and cell cycle disruption. This dysfunction could possibly be the basis for dysfunction in human diseases presenting abnormal nuclear morphology (Stephens et al., 2019 Curr Opin Cell Bio). Further we find that a native mechanosensitive response of the cell can be used to rescue nuclear mechanics, morphology, and function through chromatin-based rigidity (Stephens et al., 2019 MBoC). Our work continues investigations aimed at uncovering the mechanical basis of nuclear shape and the functional consequences of loss of nuclear shape and compartmentalization.
Gladstein S, Almassalha LM, Cherkezyan L, Chandler JE, Eshein A, Eid A, Zhang D, Wu W, Bauer GM, Stephens AD, Morochnik S, Subramanian H, Marko J, Ameer GA, Szleifer I, Backman V. (2018). Multimodal interferometric imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm. Nat Commun. 10(1) 1652. https://www.nature.com/articles/s41467-019-09717-6
Stephens AD*, Liu PZ*, Kandula V, Chen H, Herman C, Almassahla LM, O’Halloran T, Backman V, Adam S, Goldman R, Banigan EJ, Marko JF. (2018). Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation. * co-first authors. Mol Biol Cell E19-05-0286-T. https://www.molbiolcell.org/doi/10.1091/mbc.E19-05-0286
Stephens AD, Banigan EJ, Marko JF. (2019) Chromatin’s physical properties shape the nucleus and its functions. Curr Opin Cell Biol. 58:76-84. https://authors.elsevier.com/c/1YkAi3PA3sD5G3
Biggs R, Liu P, Stephens AD, Marko F. (2019). Effects of altering histone post-translational modifications on mitotic chromosome structure and mechanics. Mol Biol Cell. 30:820-827. https://www.molbiolcell.org/doi/10.1091/mbc.E18-09-0592.
Stephens AD, Liu PZ, Banigan EJ, Almassahla LM, Backman V, Adam S, Goldman R , Marko JF. (2018). Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell. 29: 220-233. http://www.molbiolcell.org/content/29/2/220.abstract
Stephens AD, Banigan EJ, Marko JF . (2017). Separate roles for chromatin and lamins in nuclear mechanics. Nucleus. Dec 28:1-6. http://www.tandfonline.com/eprint/XjQ2r86HruFEyHqfHAhu/full
Banigan EJ, Stephens AD, Marko JF. (2017). Mechanics and buckling of biopolymeric shells and cell nuclei. Biophys J. 8: 1654-1663. http://www.sciencedirect.com/science/article/pii/S0006349517309293
Stephens AD,Banigan EJ, Adam S, Goldman R, Marko JF. (2017). Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus. Mol Biol Cell. 28: 1984-1996. http://www.molbiolcell.org/content/28/14/1984.full