Nuclear Organization Through Phase Separation: Mechanisms, Functions and Disease

Many of the internal structures in our cells, or organelles, are separated by thin membranes, like small balloons within the larger balloon that is the entire cell. These separations allow different regions of the cell to carry out specialized functions, without mixing molecules with other structures in the cell. In the past several years, researchers have come to appreciate that the cell has other ways to separate its compartments that rely not on membranes, but on a process named phase separation, similar to the way oil and vinegar separate in a salad dressing. In the nucleus, the DNA-storage compartment of the cell, these phase separated compartments, also known as biomolecular condensates, appear to be especially important for how cells turn their genes on and off and how they repair their DNA when it is damaged. Michael Rosen and his team will probe the chemical properties that allow certain proteins to form condensates, study how phase separation alters gene activity, capture precise images of the condensates’ 3D structures, and ask how alterations in biomolecular condensates trigger a rare type of cancer. 

Affiliated Investigators

Michael Rosen, Ph.D.

The University of Texas Southwestern Medical Center

Michael Rosen is Chair of the Department of Biophysics at UT Southwestern Medical Center, where he holds the Mar Nell and F. Andrew Bell Distinguished Chair in Biochemistry and is an Investigator of the Howard Hughes Medical Institute. His lab uses biophysical techniques to understand the formation, regulation and functions of biomolecular condensates, cellular compartments that concentrate diverse but specific groups of molecules without a surrounding membrane. Applying tenets from polymer science he established multivalency-driven liquid-liquid phase separation (LLPS) as an organizing principle for biomolecular condensates. He showed that diverse multivalent molecules, including natural and engineered multidomain proteins, intrinsically disordered proteins and nucleic acids undergo liquid-liquid phase separation in vitro and in cells, forming distinct structures with unique functions. Further, he showed that assembly and disassembly of phase separated structures can be rapidly controlled by covalent modifications, elucidating a key mode of condensate regulation. Broadly, his lab illustrated how complex behaviors of condensates can be reduced to biochemically tractable problems and simple rules.

Rosen received undergraduate degrees in chemistry and in chemical engineering from the University of Michigan in 1987. He then spent a year in Alan Battersby’s lab in the Department of Chemistry at the University of Cambridge as a Winston Churchill Foundation Scholar. He received his Ph.D. in Chemistry from Harvard University in 1993 under the direction of Stuart Schreiber, where he studied the structure and function of the FK506 binding protein, FKBP12. He was a Damon Runyon-Walter Winchell post-doctoral fellow in the laboratories of Tony Pawson and Lewis Kay at the University of Toronto, where he studied regulation of the signaling adaptor protein, Crk, and developed methods of selective methyl group labeling of proteins for NMR spectroscopy. Dr. Rosen started his independent laboratory in 1996 in the Cellular Biochemistry and Biophysics Program at the Memorial Sloan-Kettering Cancer Center in New York City, and moved to UTSW in 2001.