Tian Chi, PhDProfessor

Surprisingly, although the sequences of the 20,000 mammalian protein-coding genes have been known for over 20 years, their functions in the 500 cell types remain largely enigmatic, which has constituted a key bottleneck for disease diagnosis and treatment.  Convinced that technology is the mother of scientific discoveries, we have previously developed a series of genetic tools to decipher and manipulate the genome, including those for reversible gene targeting, conditional point mutation, inducible expression, and DNA and RNA base editing^1-5, which has led to important scientific findings^2,6-7.  Our current research focuses on two areas:

1) iMAP⁸. This is a genetic strategy we recently reported that enables in situ disruption of 100 target genes across diverse cell types in mice. iMAP can also be used for cost-effective generation of 100 conventional single-gene KO lines via simple breeding. Simply put, iMAP accelerates gene function discovery 100-fold. We are seeking to boost iMAP throughput, and to couple iMAP to other forms of genetic perturbations including gene silencing, activation and base-editing. We are also seeking to establish an international consortium to map the “Perturb-Atlas” profiling the effects of perturbation of each of the 20,000 genes on the spatial transcriptome and epigenome throughput the body at the single-cell level in both adult mice and embryos. This atlas should become an indispensable reference map in functional genomics and a major milestone in the history of biomedical research. 

2) Therapeutic targets.  iMAP offers a powerful method for identifying therapeutic targets in various diseases. Our current focus is on immune-related diseases particularly cancer⁹. We have identified Hdac7 as a potent immune checkpoint gene in CD8 T cells whose disruption strongly enhances tumor killing by the human CAR-T cells⁸, and are extending the screening to other immune cells particularly NK cells.