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J. Biol. Chem., Vol. 280, Issue 24, 23340-23348, June 17, 2005

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Targeted Deletion of the Chicken -Globin Regulatory Elements Reveals a Cooperative Gene Silencing Activity^*

Jin Wang, Hui Liu, Chi Mei Lin¶, Mirit I. Aladjem¶, and Elliot M. Epner||

From the Center for Hematologic Malignancies, Oregon Cancer Institute, Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239 and the ^¶Laboratory of Molecular Pharmacology, NCI, National Institutes of Health, Bethesda, Maryland 20892

The chicken -globin locus represents a well characterized system to study the role of both proximal and distal regulatory elements in a eukaryotic multigene domain. The function of the chicken ^A/-intergenic enhancer and upstream regulatory elements 5'-HS1 and 5'-HS2 were studied using a gene targeting approach in chicken DT40 cells followed by microcell-mediated chromosome transfer into human erythroleukemia cells (K562). These regulatory elements all repressed expression of the - and ^H-chicken globin genes in the chromosome transfer assay. No - or ^H-globin gene expression was detected in K562 cells containing the chicken chromosome without deletions, whereas - and ^H-mRNA was activated in K562 cells containing chicken chromosomes with deletions of the intergenic enhancers, 5'-HS1 and 5'-HS2. Transcriptional activation of the - and ^H-globin genes correlated with hyperacetylation of histones H3 and H4, loss of histone H3 lysine 9 methylation, and binding of RNA polymerase II to the gene promoters. Surprisingly, the status of CpG dinucleotide methylation at the promoters did not correlate with the transcriptional status of the genes. Our results using a chromosomal transfer assay demonstrate an identical silencing function for these regulatory elements, which suggests they function as part of a common silencing pathway or complex.

Received for publication, February 1, 2005 , and in revised form, April 7, 2005.

^* This work was supported by National Institutes of Health Grant DK56798. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I and II.

Present address: Virginia Bioinformatics Institute, Blacksburg, Virginia 24061.

^|| To whom correspondence should be addressed. Tel.: 503-494-1551; Fax: 503-494-1552; E-mail: epnere{at}ohsu.edu.

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