All of the human β‐type globin genes compete for LCR enhancer activity in embryonic erythroid cells of yeast artificial chromosome transgenic mice

Abstract

ABSTRACT In primitive erythroid cells of human β‐globin locus transgenic mice (TgM), the locus control region (LCR)‐proximal ε‐ and γ‐globin genes are transcribed, whereas the distal δ‐ and β‐globin genes are silent. It is generally accepted that the β‐globin gene is competitively suppressed by γ‐globin gene expression at this developmental stage. Previously, however, we observed that ε‐globin gene expression was severely attenuated when its distance from the LCR was extended, implying that β‐globin gene might also be silenced because of its great distance from the LCR. Here, to clarify the β‐globin gene silencing mechanism, we established TgM lines carrying either γ‐ or ε‐ plus γ‐globin promoter deletions, without significantly altering the distance between the β‐globin gene and the LCR. Precocious expression of δ‐ and β‐globin genes was observed in primitive erythroid cells of mutant, but not wild‐type TgM, which was most evident when both the ε and γ promoters were deleted. Thus, we clearly demonstrated that the repression of the δ‐ and β‐globin genes in primitive erythroid cells is dominated by competitive silencing by the ε‐ and γ‐globin gene promoters, and that ε‐ and the other β‐like globin genes might be activated by two distinct mechanisms by the LCR.—Okamura, E., Matsuzaki, H., Campbell, A. D., Engel, J. D., Fukamizu, A., Tanimoto, K. All of the human β‐type globin genes compete for LCR enhancer activity in embryonic erythroid cells of yeast artificial chromosome transgenic mice. FASEB J. 23, 4335‐4343 (2009). www.fasebj.org