The overall goal of this research proposal is to delineate the cis control of the globin gene switching and the structure function relationships in the beta-locus control region (LCR). There are six specific aims with a number of subsidiary aims which include: 1) To develop new methodologies for using yeast artificial chromosomes (YACs) in the study of globin gene switching by producing new shorter beta-YACs which will facilitate structural analysis and by developing methods to protect high molecular weight YAC DNA from the degradation. 2) To investigate the structure functional relationship of the locus control region and its role in globin switching. 3) To examine the molecular control of epsilon globin gene expression. 4) To investigate the control of the gamma-globin gene expression. 5) To investigate the relationship between the spatial gene order and the temporal order of developmental expression of globin genes, and 6) To develop in vivo binary assays for studying trans-control of switching. It is hoped that with a better understanding of this system and transacting elements involved in globin gene control during development and differentiation, new insights will emerge which will suggest strategies for the manipulation of fetal hemoglobin expression in the treatment of patients with sickle cell anemia or beta-thalassemia syndromes.
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