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J. Biol. Chem., Vol. 283, Issue 40, 26937-26947, October 3, 2008

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A Network of Krüppel-like Factors (Klfs)

Klf8 IS REPRESSED BY Klf3 AND ACTIVATED BY Klf1 IN VIVO^*

From the School of Molecular and Microbial Biosciences, University of Sydney, Sydney, New South Wales 2006, Australia

Transcription factors of the Sp/Klf (Krüppel-like factor) family regulate biological processes such as hematopoiesis, adipogenesis, and stem cell maintenance. Here we show that Bklf or Klf3 (Basic Krüppel-like factor) represses the Klf8 (Krüppel-like Factor 8) gene in vivo. Conversely, Eklf or Klf1 (Erythroid Krüppel-like factor) activates the Klf8 gene. Klf8 is driven by two promoters, both of which contain multiple CACCC sites. Klf3 can repress Klf1-mediated activation of both promoters. Chromatin immunoprecipitation experiments confirm that Klf3 occupies both Klf8 promoters in vivo. Interestingly, in Klf3 knock-out tissue Klf1 gains access, binds, and activates both Klf8 promoters. These results demonstrate direct competition between activating and repressing Klfs in vivo. Together with previous evidence that Klf1 directly activates the Klf3 gene, the results reveal an elaborate network of cross-talk within the Klf family. The recognition of cross-regulation and potential redundancy between Klf family members is critical to the interpretation of various Klf knock-out mice and the understanding of individual Klfs in particular contexts.

Received for publication, June 25, 2008 , and in revised form, August 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL073443. This work was also supported by grants from the Australian Research Council and National Health and Medical Research Council (to M. C.). 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 Supported by the Australian Postgraduate Award.

² Present address: Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.

³ To whom correspondence should be addressed: School of Molecular and Microbial Biosciences, G08, University of Sydney, NSW 2006, Australia. Tel.: 61-2-9351-2233; Fax: 61-2-9351-4726; E-mail: m.crossley{at}mmb.usyd.edu.au.

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