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

AUGUSTA, Ga. A retired but well-preserved mechanism for regulating viruses that has worked its way into the human genome appears to modulate a switch between adult and fetal hemoglobin production, Medical College of Georgia researchers report.

That switch could be the key to more targeted therapies for sickle cell patients whose misshaped adult hemoglobin hinders its ability to deliver oxygen throughout the body. Fetal hemoglobin, on the other hand, can't take on the dysfunctional sickle shape.

After deleting the modulator, ERV-9, from laboratory mice that express human hemoglobin, MCG researchers found that red blood cells started producing dramatically more fetal hemoglobin, which would be ideal for sickle cell patients, said Dr. Dorothy Y.H. Tuan, molecular biologist in the MCG Schools of Medicine and Graduate Studies. She is corresponding author on the study published in PNAS; Dr. Wenhu Pi, assistant research scientist at MCG, is first author.

Fetal hemoglobin retrieves oxygen from the mother's blood. Shortly after birth, babies start producing adult hemoglobin, which gets oxygen from their own, newly functioning lungs.

It's a dramatic switch close to 100 percent and when researchers try to increase the level of either hemoglobin type, the other type goes down. "It's always a yo-yo. They must be competing for something," Tuan said.

She believes the competition is for transcription factors NF-Y and GATA-2, proteins that bind to and activate fetal and adult globin genes.

Tuan's lab has mounting evidence that ERV-9, currently viewed as junk DNA in the body, performs a critical function in ensuring adult hemoglobin production gets the lion's share of the transcription factors after birth.

Adult beta-globin gene expression in the genetically engineered mice went down 50 to 80 percent and fetal gamma-globin gene expression went up after removing ERV-9. "That is the ideal situation for
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Contact: Toni Baker
tbaker@mcg.edu
706-721-4421
Medical College of Georgia
Source:Eurekalert  

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