We have pioneered the use of a nuclease inactivated version of CRISPR/dCas9 in human cells to edit the epigenome or control transcription of protein coding or non-coding genes. We use dCas9 as a general RNA-guided DNA binding platform to recruit enzyme activities or protein complexes to specific target sites in the genome to execute a desired program. We have shown we can turn on (CRISPRa) and off (CRISPRi) expression of most genes encoded by the human genome. These tools allow us to mechanistically determine how epigenetic or transcriptional states determine cancer cell behavior and response to anti-cancer interventions. We will continue to use synthetic biology to build new innovative tools for editing the epigenome!

We have developed genome scale CRISPRi/a sgRNA libraries targeting protein coding and non-coding genes encoded by the human and mouse genome. We are using CRISPRi and CRISPRa screens to elucidate genes that dictate response to anti-cancer drugs or determine cancer cell properties such as metastasis or developmental plasticity. We have shown that genome scale CRISPRi/a screens reveal complementary principles of oncogene and non-oncogene addictions.

Genetic interaction maps are pairwise perturbations that measure gene epistasis relationships. We are building genetic interaction maps to search for synthetic lethal gene relationships in cancer, map signaling networks and determine the functions of poorly characterized genes encoded by the human genome.