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Volume 270, Number 21, Issue of May 26, pp. 12892-12898, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Identification of Two Novel Regulatory Elements within the 5`-Untranslated Region of the Human -Globin Gene

Persis J. Amrolia , John M. Cunningham , Paul Ney , Arthur W. Nienhuis , Stephen M. Jane

Interaction between the stage selector element (SSE) in the proximal -globin promoter and hypersensitivity site 2 in the locus control region partly mediates the competitive silencing of the -globin promoter in the fetal developmental stage. We have now demonstrated that a second SSE-like element in the 5`-untranslated region of the -gene also contributes to this competitive silencing of the -gene. Utilizing transient transfection assays in the fetal erythroid cell line, K562, we have shown that the core enhancer of hypersensitivity site 2 can preferentially interact with the proximal -promoter in the absence of the SSE, completely silencing a linked -promoter. Mutation of a 20-base pair sequence of the -gene 5`-untranslated region (UTR) led to derepression of -promoter activity. A marked activation of -promoter activity was also observed with this mutation, suggesting the presence of a repressor. Fine mutagenesis dissected these activities to different regions of the 5`-UTR. The stage selector activity was localized to a region centered on nucleotides +13 to +15. Electromobility shift assays utilizing this sequence demonstrated binding of a fetal and erythroid-specific protein. The repressor activity of the 5`-UTR was localized to tandem GATA-like sites, which appear to bind a complex of two proteins, one of which is the erythroid transcription factor GATA-1. These results indicate that the 5`-UTR of the -gene contains sequences that may be important for its transcriptional and developmental regulation.

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