The restriction of globin synthesis to cells of the erythroid lineage represents a fundamental problem in molecular hematology. The transcriptional activity of the beta globin locus is controlled by four erythroid specific nuclease hypersensitive sites at the 5' end of the beta globin locus on chromosome 11. This region (LCR) is critical for maintaining the globin cluster in an active chromatin conformation. The long term goal of this project is to determine how the components of the LCR interact to provide an autonomous chromosomal domain during erythropoiesis. The transcriptional activation property of the LCR can be shared by multiple promoters on a single chromosome. Two classes of models for the mechanism of the LCR are consistent with this result. The hypersensitive sites could function either independently or as an integrated unit. In this application, distinction between the two models will be made by asking if a single hypersensitive site of the LCR can activate multiple promoters on a single chromosome. Biochemical and molecular biological approaches will also be used to test the hypothesis that the hypersensitive core represents ordered nucleoprotein complexes. Elucidating the molecular mechanism of the LCR has important practical implications for expressing genes in transgenic organisms and in human gene therapy. Understanding how the LCR functions may also help in the design of synthetic LCRs that are more effective than natural ones and could lead to new approaches to the treatment of hematologic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050107-04
Application #
2905764
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1996-07-16
Project End
2001-01-31
Budget Start
1999-07-01
Budget End
2001-01-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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