Developmental regulation of human beta-like globin gene switching is controlled by several parameters, primarily the trans-acting transcriptional milieu and cis-acting DNA elements. Molecular control of globin gene switching provides a paradigm for understanding the dynamics of mammalian gene expression during ontogeny. Unraveling the mechanisms underlying beta-like globin gene switching, particularly those involved in fetal hemoglobin F (Hb F) induction, will have enormous benefit to patients suffering from a variety of hemoglobinopathies, since the general consensus within the scientific community is that sustained expression of the gamma-globin genes in adults will be palliative to these diseases. Transactivation of fetal gamma-globin gene expression has important therapeutic application for the treatment of sickle cell anemia and Cooley's anemia, as well as certain beta-thalassemias.
The Specific Aims of this research are to (1) validate the fetal specificity of already identified trans-acting proteins that activate fetal globin synthesis using novel erythroid cell lines derived from human beta-globin locus yeast artificial chromosome (beta-YAC) transgenic mice, (2) verify the fetal specificity of the same transactivators during development in an animal model by over-expression of these proteins in beta-YAC transgenic mice, (3) develop an assay system to identify new, or test existing, pharmacologic compounds that induct fetal gamma-globin gene expression without activating adult beta-globin gene expression using simultaneous measurement of both globin gene products, and (4) clone new transcriptional activators of gamma- globin gene expression from human fetal liver or GM 979 cell cDNA libraries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK061804-01
Application #
6438457
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S3))
Program Officer
Bishop, Terry Rogers
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$300,000
Indirect Cost
Name
University of Kansas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Peterson, Kenneth R; Costa, Flávia C; Fedosyuk, Halyna et al. (2014) A cell-based high-throughput screen for novel chemical inducers of fetal hemoglobin for treatment of hemoglobinopathies. PLoS One 9:e107006
Tschulena, Ulrich; Peterson, Kenneth R; Gonzalez, Beatriz et al. (2009) Positive selection of DNA-protein interactions in mammalian cells through phenotypic coupling with retrovirus production. Nat Struct Mol Biol 16:1195-9
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
Blau, C Anthony; Peterson, Kenneth R (2006) Establishment of cell lines that exhibit correct ontogenic stage-specific gene expression profiles from tissues of yeast artificial chromosome transgenic mice using chemically induced growth signals. Methods Mol Biol 349:163-73
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
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

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