The human globin genes provide a very useful model for the study of the factors involved in regulation of gene expression. Studies of mutant beta-thalassemia genes have ellucidated numerous mechanisms by which mutations can decrease or abolish gene expression in eukaryotic cells. Studies of delta beta-thalassemia and hereditary persistence of fetal hemoglobin on the other hand, have ellucidated mechanisms by which promoter mutations may lead to increased expression of the involved genes. However, the most difficult question which remains unanswered relates to the study of the factors involved in the developmental switch from fetal to adult globin production. We will attempt to shed some light on this phenomenon by studying a very unique human disorder where both fetal globin genes (G gamma and A gamma) are over-expressed in adult life in the absence of a major deletion in the beat-globin gene cluster. We have already characterized the phenotype of this condition in detail and described a promoter mutation in the beta- globin gene on the delta beta-thalassemia chromosome. We propose to search for the mutation(s) responsible for the failure of the switch from fetal to adult globin production on the involved chromosome. Another important aspect of gene regulation is the interaction of the different gene promoters and enhancers which results in tissue- specific and stage-specific gene expression. We have identified important differences in the enhancer requirement of the alpha- and beta-globin gene promoters. We propose to search for an endogenous enhancer in the alpha-globin gene and test its tissue-specificity in relevant cell lines. Hopefully, the insights obtained from such studies which utilize experiments of nature (delta beta- thalassemia) and experiments utilizing in vitro manipulations of human genes will serve to advance our understanding of the process of gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL042919-01
Application #
3361287
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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