Regulators of hemoglobin switching in zebrafish and human models

Abstract

Hemoglobin switching is a developmental process involving the dynamic transcriptional regulation of multiple globin genes. This molecular process involves multiple layer of complexity, and elucidating new mechanisms in this process will result in a more complete understanding of general gene regulation and will likely have direct clinical implications for hemoglobinopathies, such as sickle cell anemia. In this dissertation, I develop and characterize a new model for hemoglobin switching, the zebrafish. I defined and fully annotated the two zebrafish globin loci, termed major and minor loci. Both loci contain α– and β–genes oriented in a head–to–head fashion. Characterization of the globin expression pattern precisely defined the timing of normal switching and demonstrated that zebrafish, like humans, have two globin switches. The locus control region for the major locus was identified and in conjunction with a proximal promoter was able to generate robust, erythroid–specific expression in a transgenic line.