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Molecular and Cellular Biology, June 2008, p. 3967-3978, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01942-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Basic Krüppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis {triangledown} ,{dagger}

Nancy Sue,1,{ddagger} Briony H. A. Jack,1 Sally A. Eaton,1 Richard C. M. Pearson,1 Alister P. W. Funnell,1 Jeremy Turner,1 Robert Czolij,1 Gareth Denyer,1 Shisan Bao,2 Juan Carlos Molero-Navajas,3 Andrew Perkins,4 Yuko Fujiwara,5 Stuart H. Orkin,5 Kim Bell-Anderson,1 and Merlin Crossley1*

School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW 2006, Australia,1 School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia,2 Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia,3 Institute for Molecular Bioscience, Queensland Bioscience Precinct, University of Queensland, Brisbane, QLD 4072, Australia,4 Dana Farber Cancer Institute, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts5

Received 28 October 2007/ Returned for modification 5 January 2008/ Accepted 27 March 2008

Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebp{alpha} promoter. We find that C/ebp{alpha} is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebp{alpha} promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.

* Corresponding author. Mailing address: School of Molecular and Microbial Biosciences, G08, University of Sydney, Sydney, NSW 2006, Australia. Phone: 61 2 9351 2233. Fax: 61 2 9351 4726. E-mail: m.crossley{at}mmb.usyd.edu.au

{triangledown} Published ahead of print on 7 April 2008.

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

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

Molecular and Cellular Biology, June 2008, p. 3967-3978, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01942-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chen, S., Whetstine, J. R., Ghosh, S., Hanover, J. A., Gali, R. R., Grosu, P., Shi, Y. (2009). The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span. Proc. Natl. Acad. Sci. USA 106: 1496-1501 [Abstract] [Full Text]  
  • Eaton, S. A., Funnell, A. P. W., Sue, N., Nicholas, H., Pearson, R. C. M., Crossley, M. (2008). A Network of Kruppel-like Factors (Klfs): Klf8 IS REPRESSED BY Klf3 AND ACTIVATED BY Klf1 IN VIVO. J. Biol. Chem. 283: 26937-26947 [Abstract] [Full Text]  


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