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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4223-4228.
Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-02-0574.
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RED CELLS
Role of AP1/NFE2 binding sites in endogenous  -globin gene transcription
Melanie R. Loyd,
Yasuhiro Okamoto,
Mindy S. Randall, and
Paul A. Ney
From the Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN.
High-level  -globin expression depends on cis-acting regulatory sequences located far upstream of the -globin cluster. Sequences that contain the -globin positive regulatory element (PRE) activate -globin expression in transgenic mice. The -globin PRE contains a pair of composite binding sites for the transcription factors activating protein 1 and nuclear factor erythroid 2 (AP1/NFE2). To determine the role of these binding sites in -globin gene transcription, we mutated the AP1/NFE2 sites in the -globin PRE in mice. We replaced the AP1/NFE2 sites with a neomycin resistance gene (neo) that is flanked by LoxP sites (floxed). Mice with this mutation exhibited increased embryonic death and -thalassemia intermedia. Next, we removed the neo gene by Cre-mediated recombination, leaving a single LoxP site in place of the AP1/NFE2 sites. These mice were phenotypically normal. However, -globin expression, measured by allele-specific RNA polymerase chain reaction (PCR), was decreased 25%. We examined the role of the hematopoietic-restricted transcription factor p45Nfe2 in activating expression through these sites and found that it is not required. Thus, we have demonstrated that AP1/NFE2 binding sites in the murine -globin PRE contribute to long-range -globin gene activation. The proteins that mediate this effect remain to be determined. (Blood. 2003;102:4223-4228)
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