New models for nuclear homeostasis: integrating force, flow and pressure

How does the nucleus keep its size and shape? Megan King and Simon Mochrie are leading a collaborative team to study the physical and molecular forces that maintain the correct size of our cells’ largest organelle, the nucleus. For reasons that have long remained mysterious, the nucleus is always scaled to take up a certain percentage of a healthy cell’s volume. This measured scaling is often thrown out of whack in diseases such as cancer, but the mechanisms underlying its maintenance and why those mechanisms fail in disease remain unclear. The researchers hypothesize that nuclear pore complexes, transport channels which perforate the nuclear membranes, regulate the organelle’s size by maintaining a set level of tension and pressure.  

Affiliated Investigators

Megan King, Ph.D.

Yale University

Dr. Megan King is an Associate Professor in the Departments of Cell Biology at Yale School of Medicine and Molecular Cell and Developmental Biology at Yale University. She received her B.A. in Biochemistry from Brandeis University working with Dr. Susan Lowey on the functions of skeletal myosin light chains and her Ph.D. in Biochemistry and Molecular Biophysics from the University of Pennsylvania working with Dr. Mark Lemmon on dynamin and its antiviral cousin, MxB, which she found docks at nuclear pore complexes and influences nuclear transport. During her postdoctoral training with Dr. Günter Blobel at Rockefeller University, Dr. King discovered new mechanisms for the targeting and function of integral inner nuclear membrane proteins. Her work uncovered a critical physical network comprised of chromatin inside the nucleus, nuclear envelope membrane proteins, and the cytoplasmic cytoskeleton. Since founding her own group at Yale in 2009, Dr. King has continued to investigate the broad array of biological functions that are integrated at the nuclear envelope. Her group was the first to demonstrate that chromatin and its tethering to the nuclear envelope plays a critical role in determining the mechanical stiffness of nuclei. Her team has also made key contributions to our understanding of genome integrity pathways and mechanotransduction through the LINC complex. Dr. King was named a Searle Scholar in 2011 and is a recipient of the NIH New Innovator Award.  

Simon Mochrie, Ph.D.

Yale University

Simon Mochrie is a Professor of Physics and of Applied Physics at Yale University, where he studies the physics of living materials.  The recent focus of his research has been to bring simple theoretical and computational approaches to elucidate chromatin organization and dynamics, and to compare the resultant predictions to experimental data. In other projects, he used small-angle x-ray scattering on single insect scales to identify ordered photonic nanostructures, which insects grow by exploiting the self-organizing propensity of cellular lipid-bilayer membranes, and he showed that the folding/unfolding thermodynamics of repeat proteins can be quantitatively described by the classical one-dimensional Ising model. Throughout his career, an important feature of Simon’s research has been the introduction of novel methods, analyses, and approaches. Before engaging with biological physics, he invented, developed and exploited x-ray photon correlation spectroscopy (XPCS) to characterize the slow dynamics of polymeric and colloidal systems on shorter length scales than possible optically. This work led to the Advanced Photon Source’s Arthur H. Compton Award in 2009 and has motivated the implementation of beamlines for XPCS at synchrotron facilities around the world. He earned a BA from the University of Oxford and a PhD in Physics from the Massachusetts Institute of Technology, where he studied phase transitions in a number of systems that realize low-dimensional behavior. He then became a Member of Technical Staff at AT&T Bell Laboratories, before returning to MIT as faculty. He moved to Yale in 2000.