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Adult Stage -Globin Silencing Is Mediated by a Promoter Direct Repeat Element

Graduate School of Life and Environmental Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan,¹ Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan²

Received 23 August 2004/ Returned for modification 8 November 2004/ Accepted 7 February 2005

The human ß-like globin genes (5'--G-A--ß-3') are temporally expressed in sequential order from the 5' to 3' end of the locus, but the nonadult - and -globin genes are autonomously silenced in adult erythroid cells. Two cis elements have been proposed to regulate definitive erythroid -globin repression: the DR (direct repeat) and CCTTG elements. Since these two elements partially overlap, and since a well-characterized HPFH point mutation maps to an overlapping nucleotide, it is not clear if both or only one of the two participate in -globin silencing. To evaluate the contribution of these hypothetical silencers to -globin regulation, we generated point mutations that individually disrupted either the single DR or all four CCTTG elements. These two were separately incorporated into human ß-globin yeast artificial chromosomes, which were then used to generate -globin mutant transgenic mice. While DR element mutation led to a dramatic increase in A-globin expression only during definitive erythropoiesis, the CCTTG mutation did not affect adult stage transcription. These results demonstrate that the DR sequence element autonomously mediates definitive stage-specific -globin gene silencing.

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