The overall goal of this research proposal is to delineate the function of the LCR of the beta-globin locus using both molecular and biophysical approaches. The questions being addressed include whether the beta-globin LCR physically interacts with the individual globin gene promoters, and what the correlation is between these interactions and globin gene transcription. The proposal has three specific aims. The first specific aim will involve the production of a partially """"""""humanized"""""""" mouse in which one copy of the murine beta-globin locus will be replaced with a human beta-globin locus using cre-lox site-specific recombination technology and embryonic stem cells. This will fulfill the criteria of a single copy intact locus that can be reproducibly integrated into the same chromosomal location where the chromatin is conducive to globin gene expression.
Specific Aim 2 involves tests of the physical interaction of the LCR with the human globin gene using fluorescence resonance energy transfer (FRET).
Specific Aim 3 will test the role of the LCR sequences in LCR complex formation and globin gene regulation using transgenic mice containing mutant beta-globin loci by applying FRET.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
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University of Kansas
Schools of Medicine
Kansas City
United States
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Harju-Baker, Susanna; Costa, Flavia C; Fedosyuk, Halyna et al. (2008) Silencing of Agamma-globin gene expression during adult definitive erythropoiesis mediated by GATA-1-FOG-1-Mi2 complex binding at the -566 GATA site. Mol Cell Biol 28:3101-13
Fedosyuk, Halyna; Peterson, Kenneth R (2007) Deletion of the human beta-globin LCR 5'HS4 or 5'HS1 differentially affects beta-like globin gene expression in beta-YAC transgenic mice. Blood Cells Mol Dis 39:44-55
Harju, Susanna; Navas, Patrick A; Stamatoyannopoulos, George et al. (2005) Genome architecture of the human beta-globin locus affects developmental regulation of gene expression. Mol Cell Biol 25:8765-78
Blau, C Anthony; Barbas 3rd, Carlos F; Bomhoff, Anna L et al. (2005) {gamma}-Globin gene expression in chemical inducer of dimerization (CID)-dependent multipotential cells established from human {beta}-globin locus yeast artificial chromosome ({beta}-YAC) transgenic mice. J Biol Chem 280:36642-7
Harju, Susanna; Fedosyuk, Halyna; Peterson, Kenneth R (2004) Rapid isolation of yeast genomic DNA: Bust n' Grab. BMC Biotechnol 4:8
Peterson, Kenneth R (2003) Transgenic mice carrying yeast artificial chromosomes. Expert Rev Mol Med 5:1-25
Peterson, Kenneth R (2003) Hemoglobin switching: new insights. Curr Opin Hematol 10:123-9
Li, Qiliang; Peterson, Kenneth R; Fang, Xiangdong et al. (2002) Locus control regions. Blood 100:3077-86
Harju, Susanna; McQueen, Kellie J; Peterson, Kenneth R (2002) Chromatin structure and control of beta-like globin gene switching. Exp Biol Med (Maywood) 227:683-700
Navas, P A; Peterson, K R; Li, Q et al. (2001) The 5'HS4 core element of the human beta-globin locus control region is required for high-level globin gene expression in definitive but not in primitive erythropoiesis. J Mol Biol 312:17-26

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