Assembling DNA into chromatin

Clodagh O’Shea will tackle how the assembly of DNA into chromatin, the protein packaging system that compacts a six-foot-long string of DNA into a microscopically small nucleus, determines how drugs function, fuels cancer and drives everything about our biology. O’Shea proposes that DNA assembles highly flexible chromatin chains that adapt many different shapes and at critical concentration densities in the nucleus change states between liquids and gels. In the liquid, less concentrated state, genes are loosely bundled into dilute chromatin and can be easily accessed by proteins and read out into their protein products. In the more concentrated, gel-like phase, tightly-packed DNA keeps genes locked away and silenced. Her project will test this theory using a newly developed chromatin “paint” called ChromEMT that illuminates DNA’s 3D chromatin shape and interactions in the nucleus of intact cells and tissues. Using these new technologies, her team will ask if liquid-to-gel chromatin state transitions determine genomic DNA activity, and ultimately cell fate, in response to epigenetic drugs, aging, cancer-causing genes and viruses.

Affiliated Investigators

Clodagh O’Shea, Ph.D.

Salk Institute for Biological Studies

Clodagh O’Shea is the Wicklow Capital Endowed Chair and a Professor of Molecular and Cell Biology at the Salk Institute as well as a Howard Hughes Medical Institute Faculty Scholar. Her research integrates cancer biology, systems virology, structural biology, multi-modal imaging, synthetic biology and genomics to reveal critical growth regulatory targets and translate this knowledge into precision medicines. Her work has revealed the profound overlap between the cellular networks and targets disrupted in viral and cancer replication, which she is exploiting to design synthetic viral vectors, vaccines and cancer therapies. Her team has also developed disruptive new genome assembly and imaging technologies, such as Adsembly and ChromEMT. ChromEMT enables chromatin structure and 3D organization to be reconstructed  at nucleosome resolutions and megabase scales, which has revealed fundamental new insights into genome structure-function in the nucleus. Dr. O’Shea received her Bachelor’s degree in Biochemistry from the University College Cork and her Ph.D. in Immunology at the I.C.R.F. in London. She was a HFSP fellow in Dr. Frank McCormick’s laboratory at the UCSF Cancer Center where she worked on the prototype for oncolytic viral therapy. She has received numerous awards for her research, including the Beckman Young Investigator Award, the Sontag Distinguished Scientist Award, the American Cancer & Gene Therapy Young Investigator Award, Kavli Frontiers Fellow, and the W.M. Keck Medical Research Award.