Medical Research

Salk Institute for Biological Studies

Clodagh O'Shea, Mark Ellisman
La Jolla, CA
$1,000,000
June 2014

To fit within the nucleus, DNA assembles into chromatin and coils into spatially defined territories that determine if genes are active or silent through poorly understood mechanisms.  The higher order coding structures of the human genome have not been visualized within an intact cell and remain one of the most intractable challenges in biology.  To overcome this, PI Clodagh O’Shea has identified a cell permeable fluorescent small molecule that binds specifically to DNA and upon excitation can be used to paint its surface with an electron dense polymer that enables the 3D ultrastructure of chromatin to be visualized at nucleosome resolutions.  O’Shea and UCSD co-PI Mark Ellisman will combine this technique, called ChromEM, with metal nanoparticles targeted to specific genes.  They will apply the combined technology to visualize how viruses cause rearrangement of the 3D chromatin structure in the infected cell’s nucleus to modulate gene activity.  If successful, the methodology would reveal important clues to the relationship between chromatin structure and gene expression.  These technological innovations and conceptual advances will have exciting applications that impact many aspects of biomedical science.

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