What underlies diverse human traits? Why are some of us at a higher risk of developing certain diseases? How does genetic and epigenetic mechanisms regulate cell fate decisions in human development?
The Huangfu lab seeks to decode complex human disease trait through understanding the roles of genes and variants and their interactions with the environment. Our primary focus revolves around pancreas development and diabetes – a pressing global health issue. We use human pluripotent stem cells (hPSCs), including hESCs and hiPSCs, to recapitulate pancreas development and diabetes-relevant cell types. Our approach is multi-faceted, employing a range of strategies that encompass natural genetic perturbations (examining genetic variants in noncoding regions inherent to individuals' genetic makeup), deliberate experimental genetic perturbations (inclusive of CRISPR-Cas9 editing, CRISPR interference, and CRISPR activation), and exposure to stress-mimicking environmental conditions. To characterize the impact of these diverse perturbations, we conduct a variety phenotypic assay including scRNA-seq and Perturb-seq (combining CRISPR perturbation with scRNA-seq). These approaches have led us to discover many new genes and enhancer elements involved in the regulation of human pancreas biology, as well as fundamental epigenetic regulatory mechanisms (e.g., DNA methylation). In future studies, we aim to further deepen the understanding of the genes, variants, and environmental factors that contribute to cellular phenotypes and affect diabetes risks, thus informing the development of new therapies and preventive measures.
- Genetic screens via CRISPR
- Enhancer discovery
- DNA methylation
The ability to program naïve cells or to reprogram differentiated cells into particular fates will open the door to the discovery of novel therapeutics for diseases such as diabetes. The goal of my lab is to understand the fundamental principles that govern the identity of a cell, and to use these principles to manipulate cell fates for regenerative medicine. In pursuit of this goal, we employ a variety of approaches including cellular programming and reprogramming through gene transduction, directed differentiation of embryonic stem (ES) cells, chemical screening, mouse genetics, adult tissue injury and regeneration, and tissue/cell transplantation.
- Helen Hay Whitney Postdoctoral Fellowship (2006)
- Discovered the role of cilium in Hedgehog signal transduction
- Large-scale CRISPR screening in hPSCs
- Leading MorPhiC efforts to define null allele phenotypes in human cells