Harnessing RNA Regulation to Direct Protein Evolution and Control Mammalian Gene Expression

Speaker:

Bryan C. Dickinson, Department of Chemistry - University of Chicago

 

Description:

I will present two recent technologies our group has developed that
harness RNA regulation – one for basic science purposes and one for
therapeutic development. First, I will describe new methods that use
our RNA polymerase-based biosensors to harness evolution in order to
probe the emergence of “selectivity” between biomolecular interfaces,
in particular, protein-protein interactions (PPIs). Using a
combination of high-throughput biochemical methods, ancestral
reconstruction, and a new rapid evolution technology, we developed a
model system involving the BCL-2 family of apoptotic regulatory
proteins to probe fundamental evolutionary questions about PPIs and
how selectivity (or not) emerges between them. In the second half of
the talk, I will discuss therapeutic opportunities involving RNA
regulation and “epitranscriptomics”. While RNA regulation offers
exciting opportunities to create genetic therapies that are reversible
and tunable, most current approaches rely on large,
microbially-derived systems that pose clinical challenges. We
developed the CRISPR/Cas-inspired RNA targeting system (CIRTS), a new
protein engineering strategy for constructing programmable RNA
regulatory systems entirely from human protein parts. The small size
and human-derived nature of CIRTS provides a less-perturbative method
for fundamental studies as well as a potential strategy to avoid
immune issues when applied to epitranscriptomic therapies.