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Molecular and Cellular Biology, May 2005, p. 3864-3874, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3864-3874.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Human ß-Globin Locus Control Region Can Silence as Well as Activate Gene Expression

Department of Medicine, Division of Hematology, and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York,¹ Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland²

Received 17 September 2004/ Returned for modification 25 October 2004/ Accepted 1 March 2005

Using recombinase-mediated cassette exchange to test multiple transgenes at the same site of integration, we demonstrate a novel chromatin context-dependent silencer activity of the ß-globin locus control region (LCR). This silencer activity requires DNase I hypersensitive sites HS2 and HS3 but not HS4. After silencing, the silenced cassettes adopt a typical closed chromatin conformation (histone H3 and H4 deacetylation, histone H3-K4 methylation, DNA methylation, and replication in late S phase). In the absence of the LCR at the same site of integration, the chromatin remains decondensed. We demonstrate that the LCR is necessary but not sufficient to trigger these chromatin changes. We also provide evidence that this novel silencing activity is caused by transcriptional interference triggered by activation of transcription in the flanking sequences by the LCR.

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