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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK045365-08
Application #
2905497
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1992-09-30
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hughey, Jeffery R; Du, Meijun; Li, Qiliang et al. (2012) A search for ? thalassemia mutations in 4000 year old ancient DNAs of Minoan Cretans. Blood Cells Mol Dis 48:7-10
Fang, Xiangdong; Yin, Wenxuan; Xiang, Ping et al. (2009) The higher structure of chromatin in the LCR of the beta-globin locus changes during development. J Mol Biol 394:197-208
Olave, Ivan A; Doneanu, Catalin; Fang, Xiangdong et al. (2007) Purification and identification of proteins that bind to the hereditary persistence of fetal hemoglobin -198 mutation in the gamma-globin gene promoter. J Biol Chem 282:853-62
Li, Qiliang; Fang, Xiangdong; Olave, Ivan et al. (2006) Transcriptional potential of the gamma-globin gene is dependent on the CACCC box in a developmental stage-specific manner. Nucleic Acids Res 34:3909-16
Yu, Man; Han, Hemei; Xiang, Ping et al. (2006) Autonomous silencing as well as competition controls gamma-globin gene expression during development. Mol Cell Biol 26:4775-81
Cao, Hua; Jung, Manfred; Stamatoyannopoulos, George (2005) Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce gamma gene expression in vivo. Exp Hematol 33:1443-9
Fang, Xiangdong; Sun, Jin; Xiang, Ping et al. (2005) Synergistic and additive properties of the beta-globin locus control region (LCR) revealed by 5'HS3 deletion mutations: implication for LCR chromatin architecture. Mol Cell Biol 25:7033-41
Xiang, Ping; Han, Hemei; Barkess, Grainne et al. (2005) Juxtaposition of the HPFH2 enhancer is not sufficient to reactivate the gamma-globin gene in adult erythropoiesis. Hum Mol Genet 14:3047-56
Cao, Hua; Stamatoyannopoulos, George; Jung, Manfred (2004) Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood 103:701-9
Fang, Xiangdong; Han, Hemei; Stamatoyannopoulos, George et al. (2004) Developmentally specific role of the CCAAT box in regulation of human gamma-globin gene expression. J Biol Chem 279:5444-9

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