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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2924-2933
Alterations in Protein-DNA Interactions in the  -Globin Gene
Promoter in Response to Butyrate Therapy
Tohru Ikuta,
Yuet Wai Kan,
Paul S. Swerdlow,
Douglas V. Faller, and
Susan P. Perrine
From the Hemoglobinopathy-Thalassemia Research Unit and Cancer
Research Center, Departments of Pharmacology and Experimental
Therapeutics, Pediatrics, and Medicine, Boston University School of
Medicine, Boston, MA; the Department of Medicine, Wayne State
University School of Medicine, Detroit, MI; and the Howard Hughes
Medical Institute, University of California, San Francisco, CA.
The mechanisms by which pharmacologic agents stimulate  -globin
gene expression in  -globin disorders has not been fully established at the molecular level. In studies described here, nucleated
erythroblasts were isolated from patients with -globin disorders
before and with butyrate therapy, and globin biosynthesis, mRNA, and
protein-DNA interactions were examined. Expression of -globin mRNA
increased twofold to sixfold above baseline with butyrate therapy in 7 of 8 patients studied. A 15% to 50% increase in -globin protein synthetic levels above baseline globin ratios and a relative decrease in -globin biosynthesis were observed in responsive patients. Extensive new in vivo footprints were detected in
erythroblasts of responsive patients in four regions of the -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,  CP2,
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 -globin gene expression is being
altered strongly suggest that nuclear protein binding, including
CP2, to the BRE-G1 region of the -globin gene promoter mediates
butyrate activity on -globin gene expression.
© 1998 by The American Society of Hematology.
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