Research Program

The aim of our TCNP technology project is to develop improved methods to perform synthetic lethality analysis on microarrays (SLAM) to identify genetic interactions among proteins in yeast and thus to define networks and pathways of interacting proteins. The special focus of the new technology is on developing methods for essential gene mutants (such as Ts and hypomorphic alleles, which can be systematically generated) or special mutants such as mutations at sites of modification. This complements other work we are doing in which loss of function or null alleles in nonessential genes are examined for genetic interactions. We are also planning to perform, in collaboration with the driving biological projects, systematic high copy screens in Ts mutants in the essential genes involved in lysine modification. 

A major effort revolves around systematically mutating all sites at which the four core histones are modified and assessing the phenotypic consequences. Once a complete collection is in hand, we hope to use SLAM technology to build a genetic interaction map for the nucleosome. Joel Bader plays a major role in the resultant network analysis in this project as director of our computational core. His group is also taking responsibility for a histone mutation database, the first of its kind, which will integrate systematic information on mutant phenotypes, sites of modification and other important data on histones.  We are also taking step to advance SLAM and related technologies, currently only applicable in yeast, into human systems.

Finally, the lab is collaborating extensively with driving biological projects led by Shelley Berger on histone modifications of various types, and with Cecile Pickart’s group on elucidating networks and pathways of ubiquitylation and SUMOylation. We are also collaborating with Phil Cole on networks and pathways of protein acetylation and Cynthia Wolberger on dissection of deacetylation pathways.