The human hemoglobinopathies comprise the largest class of human genetic diseases. Those involving the b-locus include b-thalassemia and sickle cell disease. Experimental results from a variety of approaches indicate clinical strategies designed to achieve increased levels of fetal hemoglobin in the erythrocytes of people with these diseases would achieve significant clinical benefits. While several - strategies have been employed or are under development, no routinely applicable safe and effective method for activating g-globin gene expression has been devised. A clear understanding of the mechanisms by which the g-globin gene is silenced during development or reactivated in specific genetic conditions is a direct route to identifying targets for the rational design of therapies directed at g-globin gene re-expression. For the development of this project we have chosen to focus on the role of chromatin structure. Strong evidence has been developed over the last three decades implicating chromatin structural changes in gene silencing in general and within the b-globin locus in particular. Recent advances in the field of chromatin structure have made this an opportune time to begin to investigate the mechanisms behind the changes in chromatin structure associated with g-globin gene silencing. By precisely identifying the changes that occur and the molecules that mediate these changes, it is our goal to identify molecular targets for future pharmacologic or genetic treatments of the b-hemoglobinopathies. In this application we propose to take a focused approach to documenting and understanding the chromatin structural changes which occur within the g-globin gene promoter during the silencing of the human g-globin gene.
AIM 1 : To comprehensively characterize g-globin promoter chromatin structure in human fetal liver in adult erythroid cells.
AIM 2 : To determine whether a human b-globin YAC transgenic mouse accurately recapitulates the chromatin structural changes associated with g-globin gene silencing seen in human cells.
AIM 3 : To begin to determine the molecular mechanisms which mediate changes in the chromatin structure of the g-globin promoter during gene silencing.
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