DNA elements within BCL11A and its target sequences in globin switching, with Stuart Orkin
Department of Hematology and Oncology, Boston Childrens Hospital, Boston, Massachusetts
This project aims to identify cellular mechanisms contributing to elevation of fetal hemoglobin (HbF, ?2?2) levels, the most promising therapy for patients with sickle cell disease. The characterization of BCL11A, a repressor of HbF production, and potential BCL11A targets within the ?-globin locus, will impact therapy design and treatment of the major hemoglobin disorders whose global health burden is rising. Although BCL11A is dispensable for normal red cell function, studies in mice have determined that it is required for development, presenting a potential obstacle for therapies designed to inhibit BCL11A function by small molecule. Aim1 will determine the dependence of BCL11A erythroid expression on a single nucleotide polymorphism dense region, identified by genome wide association studies. Aim2 will identify a region required for ?-globin gene repression within the A?-? intergenic region of the ?-globin locus. Both aims will utilize DNA targeting of mouse embryonic stem cells and analysis of BCL11A expression and/or globin gene expression in fetal and adult mice. These studies will contribute to a fuller understanding of ?-globin gene regulation, provide in vivo models for molecular characterization of hemoglobin switching, and identify erythroid specific targets for therapeutic intervention.