Since the expression of globin genes is regulated in both a temporal and tissue-specific manner, the globin gene family represents a model system for the study of gene regulation in mammalian development. Insights into the molecular basis of hemoglobin switching may also lead to new therapies for inherited anemias such as sickle cell disease and beta- thalassemia. We have recently identified a DNA binding factor (pyr factor, or PYR-F) which is restricted to blood cells late in development and which binds to a putative regulatory site for fetal-to-adult globin gene switching. The PYR-F binding site is capable of adopting a complex secondary structure composed of triple-and single-stranded segments (H- DNA), which is believed to be important in gene regulation. The highly restricted tissue- and developmental stage-specific pattern of PYR-F DNA binding activity, the location of its binding site, and the ability of the binding site to adopt a non-B DNA structure suggests that PYR-F may function in hematopoietic cell development and hemoglobin switching. This proposal outlines a plan to determine the structure and function of PYR-F by: (1) studying the effect of deleting the PYR-F binding site on the control of human hemoglobin switching in transgenic mice; (2) purification of PYR-F to homogeneity, with the ultimate goal of using amino acid sequence data to obtain a cDNA clone; (3) using the mouse PYR- F cDNA clone is to isolate the human cDNA and mouse and human genomic DNA clones; and (4) studying the function of PYR-F in blood cell development by creating a targeted mutation of the PYR-F gene in mouse embryonic stem cells.
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