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J. Biol. Chem., Vol. 279, Issue 49, 51704-51713, December 3, 2004

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HS2 Enhancer Function Is Blocked by a Transcriptional Terminator Inserted between the Enhancer and the Promoter^*

Jianhua Ling, Lincoyan Ainol, Ling Zhang, Xiuping Yu, Wenhu Pi, and Dorothy Tuan

From the Department of Biochemistry and Molecular Biology, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912

The HS2 enhancer in the -globin locus control region regulates transcription of the globin genes 10-50 kb away. How the HS2 enhancer acts over this distance is not clearly understood. Earlier studies show that in erythroid cells the HS2 enhancer initiates synthesis of intergenic RNAs from sites within and downstream of the enhancer, and the enhancer-initiated RNAs are transcribed through the intervening DNA into the cis-linked promoter and gene. To investigate the functional significance of the enhancer-initiated transcription, here we inserted the lac operator sequence in the intervening DNA between the HS2 enhancer and the -globin promoter in reporter plasmids and integrated the plasmids into erythroid K562 cells expressing the lac repressor protein. We found that the interposed lac operator/repressor complex blocked the elongation of enhancer-initiated transcription through the intervening DNA and drastically reduced HS2 enhancer function as measured by the level of mRNA synthesized from the -globin promoter. The results indicate that the tracking and transcription mechanism of the HS2 enhancer-assembled transcriptional machinery from the enhancer through the intervening DNA into the cis-linked promoter can mediate enhancer-promoter interaction over a long distance.

Received for publication, April 12, 2004 , and in revised form, September 7, 2004.

^* This work was supported by National Institutes of Health Grants HL39948 and HL62308. 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 Figs. S1-S3 and supplemental Table S1.

To whom correspondence should be addressed. Tel.: 706-721-0272; Fax: 706-721-6608; E-mail: dtuanlo{at}mail.mcg.edu.

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