Andrew Stephens

B.S. Biology, University of Missouri - Kansas City

Ph.D. Biology, University of North Carolina - Chapel Hill

The cell nucleus must properly resist and respond for forces for faithful chromatin organization and mechanotransduction which dictate overall transcription and thus the majority of cellular behavior. During differentiation nuclear shape and rigidity change to adapt to new environments and new chromatin organization profiles. In many human diseases abnormal nuclear shape and mechanics are hallmarks of and contribute to nuclear and cellular dysfunction. While we have known about these changes for nearly a century, we still do not understand the mechanical basis behind these changes or the functional consequences. I have developed a novel force measurement technique to isolate, stretch, and determine the force response of a single mammalian nucleus via micromanipulation using micropipettes. We find that a nucleus with decreased rigidity due to decondensed chromatin, via histone modification state, causes abnormal nuclear morphology that leads to rupturing of the nucleus which causes nuclear dysfunction through DNA damage.

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(link is external)

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(link is external)

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(link is external)

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(link is external).

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(link is external)

*** We were also highlighted and got the cover!

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(link is external)

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(link is external)

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(link is external)

Stephens AD, Snider CE, Bloom K. (2015). The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation. Cell Cycle. 14: 2206-2218.  http://www.tandfonline.com/doi/full/10.1080/15384101.2015.1046656(link is external)

Snider CE, Stephens AD, Kirkland JG, Hamdani O, Kamakaka RT, Bloom K. (2014) Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis. J Cell Biol. 201405028. http://jcb.rupress.org/content/early/2014/10/14/jcb.201405028(link is external)

Verdaasdonk JS, Stephens AD, Haase J, Bloom K. (2014). Bending the rules: widefield microscopy and the Abbe limit of resolution. J Cell Physiol. 229: 132-138.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076117/(link is external)

Stephens AD, Quammen CW, Chang B, Haase J, Taylor 2nd RM, Bloom K. (2013). The spatial segregation of pericentric cohesin and condensin in the mitotic spindle. Mol Biol Cell. 23: 2560-2570.  http://www.molbiolcell.org/content/24/24/3909.full(link is external)

Stephens AD, Snider CE, Haase J, Haggerty RA, Vasquez PA, Forest GM, Bloom K. (2013). Individual pericentromeres display coordinated motion and stretching in the yeast spindle. J Cell Biol. 203: 407-16.  http://jcb.rupress.org/content/early/2013/10/28/jcb.201307104(link is external)

Haase J, Mishra PK, Stephens A, Haggerty RA, Quammen C, Taylor 2nd RM, Yeh E, Basrai MA, Bloom K. (2013). A 3D map of the yeast kinetochore reveals the presence of core and accessory centromere-specific histone. Curr. Biol. 23: 1939-1944.  http://www.sciencedirect.com/science/article/pii/S096098221300972X(link is external)

Stephens AD, Haggerty RA, Vasquez PA, Vicci L, Snider CE, Shih F, Quammen C, Mullins C, Haase J, Taylor 2nd RM, Verdaasdonk JS, Falvo M, Jin Y, Forest G, Bloom K. (2013). Pericentric chromatin loops function as a nonlinear spring in mitotic force balance. J Cell Biol. 200: 757- 72.   http://jcb.rupress.org/content/200/6/757.full(link is external)

Verdaasdonk JS, Gardner R, Stephens AD, Yeh E, Bloom K. (2012). Tension-dependent nucleosome remodeling at the pericentromere in yeast. Mol Biol Cell. 23: 2560-2570.  http://www.molbiolcell.org/content/23/13/2560.full(link is external)

Haase J, Stephens A, Verdaasdonk J, Yeh E, Bloom K. (2012). Bub1 kinase and Sgo1 modulate pericentric chromatin in response to altered microtubule dynamics. Curr Biol. 22: 471-481.  http://www.sciencedirect.com/science/article/pii/S0960982212001248(link is external)

Stephens AD, Haase J, Vicci L, Taylor 2nd RM, Bloom K. (2011). Cohesin, condensin, and the Intramolecular centromere loop together generate the mitotic chromatin spring. J Cell Biol. 193: 1167-1180.  http://jcb.rupress.org/content/193/7/1167.full(link is external)

Li Z, Vizeacoumar FJ, Bahr S, Li J, Warringer J, Vizeacoumar FS, Min R, VanderSluis B, Bellay J, DeVit M, Fleming JA, Stephens A, et al. (2011). Systematic exploration of essential yeast gene function with temperature-sensitive mutants. Nature Biotechnol. 29: 361-367.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286520/(link is external)

Bekker JM, Colantonio JR, Stephens AD, Clarke WT, King SJ, Hill KL, Crosbie RH. (2007). Direct interaction of Gas11 with microtubules: implications for the dynein regulatory complex. Cytoskeleton. 64: 461-473.  https://www.ncbi.nlm.nih.gov/pubmed/17366626(link is external)

Culver-Hanlon TL, Lex SA, Stephens AD, Quintyne NJ, King SJ. (2006). A microtubule-binding domain in dynactin increases dynein processivity by skating along microtubules. Nat Cell Biol. 8: 264.  https://www.ncbi.nlm.nih.gov/pubmed/16474384(link is external)

Links: Lab website