Overview. Regulating biological processes through controlling the proximity of participating biological molecules has been one of the most common regulatory mechanisms used by Nature. In the past years, we have developed different Chemically Induced Proximity (CIP) strategies and methods using naturally occurring or synthetic chemical ligands to control the proximity between chosen molecules and specific biological targets in cells, which allow us to regulate and study different biological processes. Following are some of our current research focuses:
New CIP systems. CIP methods use small molecule inducers to homo- or hetero-dimerize unique inducer-binding protein domains fused individually to specific proteins of interest (POIs). Depending on the chosen POIs, a wide range of downstream biological events can be rapidly triggered. These induced effects can be readily reversed by the removal of CIP inducers. As a result, CIP methods provide exceptional temporal controls, which are especially valuable in studying dynamic cellular processes. We have developed different CIP systems engineered from the plant signaling pathways including methods using abscisic acid (ABA) or indole-3-acetic acid (IAA) as the inducers, and a self-reporting system based on a fluorogenic inducer and fluorogen activating proteins.
Epigenetics. One particular interest in our lab is applying CIP strategies to control epigenetic regulation. We have developed a novel inducible epigenome editing platform integrating CIP and CRISPR technologies to achieve temporal and genome locus specific editing of histone modifications. We are currently expanding this approach to control other epigenetic pathways and to study RNA epigenetics.
Mammalian Synthetic Biology. In another research direction, we combined CIP with reactivity-based sensing technologies to create caged CIP inducers that allow us to engineer cellular signaling and reprogram how mammalian cells interface with their local environment, process the detected signals and generate tailored outputs in response. We are applying these new platforms to develop the next generation hybrid CAR T cells for treating cancer and other human diseases.
RNA Regulation. In an alternative direction of CIP strategies, we are interested in creating synthetic bi-functional molecules to control the proximity between proteins, nucleic acids and/or chemical ligands. These bi-functional molecules are designed to manipulate local concentrations of chosen molecules with unique effects at specific sites of action in cells to control particular cellular events. We are especially interested in perturbing RNA fucntions by targeting specific inhibitors or proteins to the RNAs (or associated proteins) of interest. We have applied this strategy to create bi-functional molecules that control the biogenesis of microRNAs. We are continuing to develop these alternative CIP strategies to generate novel molecules to regulate the activities and function of RNAs.
