Hemoglobin switching and fetal hemoglobin reactivation

The identification of the regulatory sequences and their complementary transcription factors provides a model of the mechanisms governing the expression of β-globinlike genes. Autonomous silencing, competition for LCR sequences, gene position, and chromatin structure are required for developmental regulation of the locus. The characterization of the stage- specific proteins EKLF and SSP, the identification of other as yet unidentified stage-specific proteins, the interactions of these molecules with components of the LCR, and the transcription initiation complex are important immediate goals. Equally important will be a determination of the developmental role of individual HS of the LCR and a deepening of our understanding of the function of chromatin structure in the expression of the genes of the locus. Results of these studies will provide possible targets for novel therapeutic strategies aimed at increasing HbF expression in adult erythroid progenitors. The dissection of the events during adult erythroid differentiation which impinge on the expression of the genes of the locus will also be crucial for the optimal use of known HbF inducers. New approaches will require the rational design of agents which take account of the expanding information on the mechanisms of hemoglobin switching and erythroid differentiation.