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Molecular and Cellular Biology, May 2005, p. 3443-3451, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3443-3451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Akane Omori,1 Osamu Tanabe,2 James Douglas Engel,2 Akiyoshi Fukamizu,1 and Keiji Tanimoto1*

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'-{varepsilon}-G{gamma}-A{gamma}-{delta}-ß-3') are temporally expressed in sequential order from the 5' to 3' end of the locus, but the nonadult {varepsilon}- and {gamma}-globin genes are autonomously silenced in adult erythroid cells. Two cis elements have been proposed to regulate definitive erythroid {gamma}-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 {gamma}-globin silencing. To evaluate the contribution of these hypothetical silencers to {gamma}-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 {gamma}-globin mutant transgenic mice. While DR element mutation led to a dramatic increase in A{gamma}-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 {gamma}-globin gene silencing.

* Corresponding author. Mailing address: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan. Phone and fax: (81) 29-853-6070. E-mail: keiji{at}tara.tsukuba.ac.jp.

Molecular and Cellular Biology, May 2005, p. 3443-3451, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3443-3451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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