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Induction of  -Globin by Histone Deacetylase Inhibitors
Patricia G. McCaffrey,
David A. Newsome,
Eitan Fibach,
Minoru Yoshida, and
Michael S.-S. Su
From the Molecular Biology Department, Vertex Pharmaceuticals Inc, Cambridge, MA; the Department of Hematology, Hadassah University Hospital, Jerusalem, Israel; Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; the Department of Biotechnology, University of Tokyo, Tokyo, Japan.
The short-chain fatty acid butyrate has been shown to elevate fetal hemoglobin (HbF ) by inducing expression of the  -globin gene. Regulation of gene expression by butyrate is thought to proceed via inhibition of the enzyme histone deacetylase, leading to elevated levels of core histone acetylation which affect chromatin structure and transcription rates. To determine whether changes in histone acetylation are critical for the regulation of the -globin gene, we tested three potent and specific inhibitors of histone deacetylase, the cyclic tetrapeptides trapoxin and Helminthsporium carbonum toxin (HC toxin), and the antifungal antibiotic trichostatin A for their ability to induce fetal hemoglobin expression in erythroid cells. These compounds induced fetal hemoglobin in both primary erythroid cell cultures and human erythroleukemia (K562) cells. A butyrate-responsive element spanning the duplicated CCAAT box region of the -globin promoter has been identified in transient transfection assays using a reporter construct in K562 cells, and we show that the same promoter region is required for response to trapoxin and trichostatin. Mutational analysis of the -globin promoter indicates that the distal CCAAT box and 3' flanking sequence (CCAATAGCC) is critical for activation by butyrate, trapoxin, and trichostatin, whereas the proximal element (CCAATAGTC) plays a less important role. These results show that inhibition of histone deacetylase can lead to transcriptional activation of -globin promoter reporter gene constructs through proximal promoter elements, and suggest that butyrate induces -globin expression via such changes in histone acetylation.
Blood, Vol. 90 No. 5 (September 1), 1997:
pp. 2075-2083
© 1997 by The American Society of Hematology.
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