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Blood. 1998 Oct 15;92(8):2924-33.

Alterations in protein-DNA interactions in the gamma-globin gene promoter in response to butyrate therapy.

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Hemoglobinopathy-Thalassemia Research Unit and Cancer Research Center, Departments of Pharmacology and Experimental Therapeutics, Pediatrics, and Medicine, Boston University School of Medicine, Boston, MA, USA.


The mechanisms by which pharmacologic agents stimulate gamma-globin gene expression in beta-globin disorders has not been fully established at the molecular level. In studies described here, nucleated erythroblasts were isolated from patients with beta-globin disorders before and with butyrate therapy, and globin biosynthesis, mRNA, and protein-DNA interactions were examined. Expression of gamma-globin mRNA increased twofold to sixfold above baseline with butyrate therapy in 7 of 8 patients studied. A 15% to 50% increase in gamma-globin protein synthetic levels above baseline gamma globin ratios and a relative decrease in beta-globin biosynthesis were observed in responsive patients. Extensive new in vivo footprints were detected in erythroblasts of responsive patients in four regions of the gamma-globin gene promoter, designated butyrate-response elements gamma 1-4 (BRE-G1-4). Electrophoretic mobility shift assays using BRE-G1 sequences as a probe demonstrated that new binding of two erythroid-specific proteins and one ubiquitous protein, alphaCP2, occurred with treatment in the responsive patients and did not occur in the nonresponder. The BRE-G1 sequence conferred butyrate inducibility in reporter gene assays. These in vivo protein-DNA interactions in human erythroblasts in which gamma-globin gene expression is being altered strongly suggest that nuclear protein binding, including alphaCP2, to the BRE-G1 region of the gamma-globin gene promoter mediates butyrate activity on gamma-globin gene expression.

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