The beta-globin genes exhibit a complicated pattern of tissue-specific, developmentally-regulated expression. They have long served as an important model for studying the regulation of complex eukaryotic gene loci. Central to the regulation of the locus is the establishment of an extended domain of erythroid-specific chromatin structures which is characterized by an overall more """"""""open"""""""" structure throughout the locus, sub-domains of generally increased accessibility to nuclease digestion and histone acetylation, and more localized regions of nuclease hypersensitivity which are associated with the regulatory elements of the locus. The long term goal of this project is to determine the compositions, mechanisms of formation and functions of the unique erythroid-specific chromatin structures of the human beta, globin gene locus. This goal is relevant not only to understanding the regulation of the beta-globin locus but also to devising new therapeutic strategies for the treatment of the human hemoglobinopathies. Manipulation of globin locus gene expression or replacement of defective globin genes through gene transfer are two strategies which offer great potential. Progress for both strategies is likely to be linked to better understanding of the regulation of the native beta-globin locus. To accomplish our goals we propose the following specific aims.
AIM 1 : To continue to characterize the formation, structure and function of the erythroid-specific human beta-globin LCR DNase I hypersensitive sites.
AIM 2 : To characterize the structure and formation of ubiquitous 5'HS5 of the beta-globin LCR.
AIM 3 : To test the ability of chromatin modifying elements to reorganize targeted domains and confer consistent, high-level, erythroid-specific gene expression on integrated globin transgenes.
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