J. Keith Joung, MD, PhD
Associate Professor of Pathology
Harvard Medical School
Associate Chief for Research
The Jim and Ann Orr MGH Research Scholar
Massachusetts General Hospital, Pathology
The Joung Laboratory develops technologies for genome engineering using artificial "designer" DNA-binding domains. We utilize engineered zinc finger, transcription activator-like effector (TALE), and RNA-guided CRISPR/Cas-based systems to direct specific genomic alterations in living cells and organisms. In addition to developing and optimizing these technologies, we are exploring their applications for biological research and gene therapy.
The Joung Laboratory seeks to develop and apply robust technologies for editing the genome and epigenome to understand human biology and treat disease. We have extensive experience with genome editing, epigenome editing, protein engineering, building and screening of large-scale combinatorial libraries, automation, and the study of protein-DNA interactions. Over the last several years, we have developed publicly available, open-source platforms for engineering zinc fingers, transcription activator-like effectors (TALEs), and clustered, regularly interspaced, short palindromic repeat (CRISPR)-Cas proteins and pioneered the use of these platforms to address important questions and limitations in biological research. We have also begun to explore the use of these platforms to modulate both gene sequence and gene expression for therapeutic applications.
Targeted genome editing using nucleases with customizable specificities
Our lab has developed highly robust methods for engineering zinc finger nucleases (ZFNs), TALE nucleases (TALENs), and CRISPR-Cas9 nucleases. Using these three platforms, we (and our collaborators) have introduced targeted DNA alterations with high efficiencies into specific genomic loci in zebrafish, plants, or human somatic and pluripotent stem cells. These alterations result from repair of nuclease-induced double-stranded DNA breaks by normal cellular repair processes (non-homologous end-joining or homologous recombination). Ongoing projects in the lab are aimed at defining and improving the specificities of these platforms and optimizing the editing capabilities of these methods for eventual therapeutic applications. We are also continuing to explore the development of novel technologies that will enable high-throughput genome editing.
Targeted epigenome editing to induce alterations in endogenous gene expression
We have demonstrated that engineered zinc fingers, TALEs, and CRISPR-Cas proteins can all be used to construct artificial transcription factors that can robustly alter the expression of endogenous human genes. More recently, we have also shown that engineered TALEs can be used to direct histone modifications that can inactivate endogenous gene enhancers (work done with Bradley Bernstein's lab) and to direct demethylation of specific promoter CpGs that can lead to increases in endogenous gene expression. These studies provide important proofs-of-principle that customized DNA targeting technologies can be used to modify the epigenome. In the longer-term, we seek to develop methods and technologies that will allow us to stably reprogram and re-wire the expression of endogenous genes in human cells. These capabilities will have important research applications for studying gene regulation but may also provide novel tools for altering the expression of disease-associated genes.
For the first year of the MGH Research Scholars Awards program, three of the five Scholars are members of MGH-HMS Pathology and the MGH Cancer Center.
MGH Hotline 6.10.11 Selected from among 115 applications from across the MGH research community, the inaugural MGH Research Scholars recently were announced at the annual meeting of the MGH Research Advisory Council (RAC).