The long-range goal of this research is to identify a feasible means to reactivate the 3-globin gene in the adult in order to ameliorate sickle cell disease and thalassemia in the patients. The objective of this competing renewal application is to understand the mechanism which governs erythroid tissue- and stage- specific globin gene regulation (hemoglobin switching). Our central hypothesis is that the 2LCR is the organizer of a transcription factory in erythroid cells;only the gene that is looped into the factory will be transcribed;the loop-in probability is determined by the chromatin flexibility, which is modulated by epigenetic changes in chromatin, e.g., histone acetylation;the transcription potential of the globin genes is not development-specific;the developmental-specific expression of the globin genes is due to the promoter-directed developmentally specific changes in histone acetylation, and consequential alteration of the preferential interaction between the LCR and the genes. This hypothesis will be tested in three specific aims. 1) To validate the hypothesis that the ?LCR is the organizer of the transcription factory specific for the globin genes in erythroid cells. 2) To test the hypothesis that the ?-globin gene promoter regulates the developmental specificity of gene expression in two separate steps. 3) To investigate the molecular events, which lead to alterations of epigenetic modifications at the ? gene promoter and the resulting modulation of chromatin looping between the LCR and the gene.

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The objective of this application is to understand the molecular mechanism which governs erythroid tissue- and stage-specific globin gene regulation (hemoglobin switching). To delineate this mechanism a facilitated chromatin looping hypothesis was put forward. Experiments were designed in three aims to test this model in this application.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Qasba, Pankaj
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Fang, Xiangdong; Xiang, Ping; Yin, Wenxuan et al. (2007) Cooperativeness of the higher chromatin structure of the beta-globin locus revealed by the deletion mutations of DNase I hypersensitive site 3 of the LCR. J Mol Biol 365:31-7
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
Yin, Wenxuan; Barkess, Grainne; Fang, Xiangdong et al. (2007) Histone acetylation at the human beta-globin locus changes with developmental age. Blood 110:4101-7
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
Li, Qiliang; Barkess, Grainne; Qian, Hong (2006) Chromatin looping and the probability of transcription. Trends Genet 22:197-202
Xiang, Ping; Fang, Xiangdong; Yin, Wenxuan et al. (2006) Non-coding transcripts far upstream of the epsilon-globin gene are distinctly expressed in human primary tissues and erythroleukemia cell lines. Biochem Biophys Res Commun 344:623-30
Li, Qiliang (2006) A Melanesian alpha-thalassemia mutation suggests a novel mechanism for regulating gene expression. Genome Biol 7:238
Yin, Wenxuan; Xiang, Ping; Li, Qiliang (2005) Investigations of the effect of DNA size in transient transfection assay using dual luciferase system. Anal Biochem 346:289-94

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