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Molecular and Cellular Biology, August 2007, p. 5286-5295, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00176-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Locus Control Region Activates Serpin Gene Expression through Recruitment of Liver-Specific Transcription Factors and RNA Polymerase II{triangledown} ,{dagger}

Hui Zhao, Richard D. Friedman, and R. E. K. Fournier*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98109

Received 30 January 2007/ Returned for modification 28 March 2007/ Accepted 16 May 2007

The human serine protease inhibitor (serpin) gene cluster at 14q32.1 comprises 11 serpin genes, many of which are expressed specifically in hepatic cells. Previous studies identified a locus control region (LCR) upstream of the human {alpha}1-antitrypsin ({alpha}1AT) gene that is required for gene activation, chromatin remodeling, and histone acetylation throughout the proximal serpin subcluster. Here we show that the LCR interacts with multiple liver-specific transcription factors, including hepatocyte nuclear factor 3ß (HNF-3ß), HNF-6{alpha}, CCAAT/enhancer binding protein alpha (C/EBP{alpha}), and C/EBPß. RNA polymerase II is also recruited to the locus through the LCR. Nongenic transcription at both the LCR and an upstream regulatory region was detected, but the deletion of the LCR abolished transcription at both sites. The deletion of HNF-3 and HNF-6 binding sites within the LCR reduced histone acetylation at both the LCR and the upstream regulatory region and decreased the transcription of the {alpha}1AT, corticosteroid binding globulin, and protein Z-dependent protease inhibitor genes. These results suggest that the LCR activates genes in the proximal serpin subcluster by recruiting liver-specific transcription factors and components of the general transcription machinery to regulatory regions upstream of the {alpha}1AT gene.

* Corresponding author. Mailing address: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109. Phone: (206) 667-5217. Fax: (206) 667-6522. E-mail: kfournie{at}fhcrc.org

{triangledown} Published ahead of print on 25 May 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5286-5295, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00176-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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