Artificial Gene Regulation by RNA Molecules

It was once believed possible that all genes were regulated by the binding of RNA molecules to the DNA double helix. This model is no longer valid, but it is interesting to explore whether artificial RNA molecules can be selected for the ability to control genes in cells. We are studying several approaches. The historical observation that transcription factor TFIIIA can bind both DNA and RNA made us curious if artificial tight-binding RNAs could be selected for other transcription factors. Expression of such RNA inhibitors in cells might down-regulate genes that respond to the target transcription factor.

Our initial studies involve small RNAs we selected for binding and inhibition of the NF-kappaB transcription factor. Inhibition of this protein could be of value against HIV-1 replication, inflammation, and in enhancing tumor cell suicide after chemotherapy, all processes involving NF-kappaB. Our work involves biochemistry with purified molecules as well as the use of genetic screens and selections with microorganisms such as bacteria and yeast. Ongoing studies seek to explore transcription factor inhibition in mammalian cells. Other research seeks to determine if RNA molecules can deliver gene regulatory proteins to new genes in cells.

X-ray crystal structure of a novel complex between NF-kappaB protein (ribbons) and two folded RNA molecules (spheres).

X-ray crystal structure of a novel complex between NF-kappaB protein (ribbons) and two folded RNA molecules (spheres).