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J. Biol. Chem., Vol. 282, Issue 29, 20868-20876, July 20, 2007

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Functional Sequestration of Transcription Factor Activity by Repetitive DNA^*

From the Diabetes Center and Department of Medicine, University of California, San Francisco, California 94143

Higher eukaryote genomes contain repetitive DNAs, often concentrated in transcriptionally inactive heterochromatin. Although repetitive DNAs are not typically considered as regulatory elements that directly affect transcription, they can contain binding sites for some transcription factors. Here, we demonstrate that binding of the transcription factor CCAAT/enhancer-binding protein (C/EBP) to the mouse major -satellite repetitive DNA sequesters C/EBP in the transcriptionally inert pericentromeric heterochromatin. We find that this sequestration reduces the transcriptional capacity of C/EBP. Functional sequestration of C/EBP was demonstrated by experimentally reducing C/EBP binding to the major -satellite DNA, which elevated the concentration of C/EBP in the non-heterochromatic subcompartment of the cell nucleus. The reduction in C/EBP binding to -satellite DNA was induced by the co-expression of the transcription factor Pit-1, which removes C/EBP from the heterochromatic compartment, and by the introduction of an altered-specificity mutation into C/EBP that reduces binding to -satellite DNA but permits normal binding to sites in some gene promoters. In both cases the loss of -satellite DNA binding coincided with an elevation in the binding of C/EBP to a promoter and an increased transcriptional output from that promoter. Thus, the binding of C/EBP to this highly repetitive DNA reduced the amount of C/EBP available for binding to and regulation of this promoter. The functional sequestration of some transcription factors through binding to repetitive DNAs may represent an underappreciated mechanism controlling transcription output.

Received for publication, March 23, 2007 , and in revised form, May 17, 2007.

^* This work was supported by National Institutes of Health Public Health Service Grant DK-54345. 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.

¹ To whom correspondence should be addressed: Diabetes Center, University of California San Francisco, S-1230, 513 Parnassus, San Francisco, CA 94143-0540. Tel.: 415-476-7086; E-mail: freds{at}diabetes.ucsf.edu.

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