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Modulator of fetal hemoglobin switch may target sickle cell disease
Date:7/12/2010

patients with sickle cell disease," Tuan said. "I think we have put our fingers on a key switching mechanism."

Without ERV-9, the adult hemoglobin gene is not as competitive for the transcription factors NF-Y and GATA-2 that it needs to be highly expressed. Still, it's a long-distance relationship: ERV-9 and the adult hemoglobin gene sit far apart on a stretch of DNA. One of Tuan's many follow-up studies is determining whether during development, ERV-9 favors the fetal hemoglobin gene, a much closer DNA neighbor.

"We want to study fetal red blood cells and see what ERV-9 is doing there," Tuan said. She also wants to better understand ERV-9's apparent ability to suppress globin genes by studying how, during development, its own DNA is chemically altered in a process called epigenetics.

DNA has four chemical bases A, G, C and T and ERV-9's DNA contains a lot of the C, or cytosine, which is easily chemically altered. The net effect of chemical alteration part of normal development is gene suppression.

If her hypothesis is correct and the fetal and adult genes are competing for NF-Y and GATA-2, what happens if there is a bigger supply of these transcription factors? "If you can increase NF-Y and GATA-2 so there is plenty around, maybe both the beta and gamma genes will be activated without one suppressing the other," Tuan said.

She has a $1.9 million grant from the National Heart, Lung and Blood Institute to further explore whether this natural mechanism she has identified might benefit sickle cell patients. There's plenty of proof that increasing fetal hemoglobin percentages helps patients. A small percentage of people with sickle cell disease, who for some unknown reason continue to express higher levels of fetal hemoglobin about 25 percent instead of the 1-2 percent expressed by most are asymptomatic, Tuan said. Typical sickle cell patients, on the other hand, suffer frequent fatigue, pain and a myriad of other
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Contact: Toni Baker
tbaker@mcg.edu
706-721-4421
Medical College of Georgia
Source:Eurekalert  

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