The human hemoglobinopathies comprise the largest class of human genetic diseases. Those involving the b-locus include b-thalassemia and sickle cell disease. Experimental results from a variety of approaches indicate clinical strategies designed to achieve increased levels of fetal hemoglobin in the erythrocytes of people with these diseases would achieve significant clinical benefits. While several - strategies have been employed or are under development, no routinely applicable safe and effective method for activating g-globin gene expression has been devised. A clear understanding of the mechanisms by which the g-globin gene is silenced during development or reactivated in specific genetic conditions is a direct route to identifying targets for the rational design of therapies directed at g-globin gene re-expression. For the development of this project we have chosen to focus on the role of chromatin structure. Strong evidence has been developed over the last three decades implicating chromatin structural changes in gene silencing in general and within the b-globin locus in particular. Recent advances in the field of chromatin structure have made this an opportune time to begin to investigate the mechanisms behind the changes in chromatin structure associated with g-globin gene silencing. By precisely identifying the changes that occur and the molecules that mediate these changes, it is our goal to identify molecular targets for future pharmacologic or genetic treatments of the b-hemoglobinopathies. In this application we propose to take a focused approach to documenting and understanding the chromatin structural changes which occur within the g-globin gene promoter during the silencing of the human g-globin gene.
AIM 1 : To comprehensively characterize g-globin promoter chromatin structure in human fetal liver in adult erythroid cells.
AIM 2 : To determine whether a human b-globin YAC transgenic mouse accurately recapitulates the chromatin structural changes associated with g-globin gene silencing seen in human cells.
AIM 3 : To begin to determine the molecular mechanisms which mediate changes in the chromatin structure of the g-globin promoter during gene silencing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073442-03
Application #
6882007
Study Section
Special Emphasis Panel (ZHL1-CSR-B (F2))
Program Officer
Evans, Gregory
Project Start
2003-04-07
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$316,000
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Schaeffer, Emily K; West, Rachel J; Conine, Sarah J et al. (2014) Multiple physical stresses induce ?-globin gene expression and fetal hemoglobin production in erythroid cells. Blood Cells Mol Dis 52:214-24
Hahn, Cynthia K; Lowrey, Christopher H (2013) Eukaryotic initiation factor 2? phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism. Blood 122:477-85
Macari, Elizabeth R; Schaeffer, Emily K; West, Rachel J et al. (2013) Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells. Blood 121:830-9
Macari, Elizabeth R; Lowrey, Christopher H (2011) Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway. Blood 117:5987-97
Boosalis, Michael S; Castaneda, Serguei A; Trudel, Marie et al. (2011) Novel therapeutic candidates, identified by molecular modeling, induce ?-globin gene expression in vivo. Blood Cells Mol Dis 47:107-16
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Hsu, Mei; Richardson, Christine A; Olivier, Emmanuel et al. (2009) Complex developmental patterns of histone modifications associated with the human beta-globin switch in primary cells. Exp Hematol 37:799-806.e4
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Mabaera, Rodwell; Greene, Michael R; Richardson, Christine A et al. (2008) Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood 111:411-20

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