Grant: Fellowship - Priority Announcement: Transfusion Science

One of the most important biomedical questions in molecular biology research is the mechanism by which gene expression is regulated in specific cell types and at specific stages of development. The globin gene family produces hemoglobin, the major protein in the red blood cell. This gene family represents an ideal model to understand how genes are regulated in complex systems and to study these mechanisms by which genes are repressed and activated at a precise time during development. Indeed, different globin genes are expressed at different stages of human life, (i.e. embryo to fetus to adult): the epsilon gene is the first gene to be expressed and is restricted to the embryonic stage; at the fetal stage the expression of epsilon is repressed and the two fetal gamma genes are activated; after birth, the gamma genes are then repressed concomitantly with the activation of two adult delta- and beta-globin genes. The shift from the use of globin chains is called the hemoglobin switch. These hemoglobin switches involve many factors that control the correct silencing and/or activation of genes in the locus. My research project focuses on the identification of these factors, the molecular interactions and understanding the in vivo mechanism(s) responsible for the fetal to adult hemoglobin switching. To elucidate this mechanism(s), I am using several new cutting-edge technologies that allow deciphering chromatin regulation and remodeling, protein complexes and network/combinatorial interactions. Understanding these molecular processes will identify key factors to prevent fetal to adult switching and thus will have important implications for patients suffering from diseases in which adult hemoglobin is not produced or is abnormal, such as in thalassemia and sickle cell disease. Our study will provide an understanding of the hemoglobin switch phenomena and the development of novel approaches for the treatment of thalassemia and sickle cell disease.