George Daley's lab focuses on stem cell biology, with an emphasis on somatic cell reprogramming, hematopoietic differentiation from human and mouse pluripotent stem cells, and common mechanisms in reprogramming and cancer. His laboratory has pioneered the study of murine and human cell culture models of leukemia and genetic bone marrow disease and the role of the Lin28/let-7 pathway in human cancer and metabolic disease.
Role of Lin28 and Its microRNA Target let-7 in Reprogramming and Cancer
Lin28A and its highly related paralog Lin28B are RNA binding proteins that are highly expressed in embryogenesis but silent in most adult tissues. Both proteins bind and inhibit biogenesis of the let-7 family of tumor suppressor microRNAs to affect cell proliferation, and also directly bind to numerous mRNAs to influence translation. We and others have implicated Lin28/let-7 in a wide range of biology, including early development, reprogramming to pluripotency, metabolism, and tumorigenesis. Much of the characterization of these proteins has focused on their interaction with the tumor suppressor miRNA let-7. We will define the distinct transcriptional regulation of the Lin28 paralogs and assess their differential roles in reprogramming, metabolism, and cancer. We will use embryonic stem cells, induced pluripotent stem cells, and Lin28-induced cancer models to dissect how Lin28/let-7 regulates cellular metabolism through binding to their mRNA and microRNA targets and how this tightly regulated metabolic program contributes to stemness and tumorigenesis. The student will work alongside a postdoctoral fellow to apply multiple techniques, including cell culture, molecular cloning, and mouse work as we probe the molecular roles of Lin28.
Use of Embryonic and Induced-Pluripotent Stem Cells for Hematopoietic Cell Generation
Transplantation of hematopoietic stem cells (HSCs) can be curative for a variety of malignant and genetic blood diseases, but the lack of matched donors and transplant-related complications limits wider application. One strategy is the creation of autologous HSCs via cellular reprogramming, because it is now feasible to generate induced-pluripotent stem cells (iPSCs) from virtually any patient and to repair gene defects via genome editing. Furthermore, we have shown that human iPSC-derived blood precursors can be converted (or respecified) into transplantable multilineage progenitors. Respecified iPSC progenitors are a particularly potent source of red blood cells in vitro and in vivo. Thus, we will use iPSC lines from patients with congenital anemias to create in vivo models of these disorders to interrogate the underlying disease mechanisms and as platforms for drug testing. The student will work alongside a postdoctoral fellow in various assays, including cell culture, molecular biology, and cellular imaging techniques, as we probe the molecular machinery of hematopoiesis.