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Molecular and Cellular Biology, September 2000, p. 6882-6890, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

beta -Catenin-Histone Deacetylase Interactions Regulate the Transition of LEF1 from a Transcriptional Repressor to an Activator

Andrew N. Billin, Hilary Thirlwell, and Donald E. Ayer*

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550

Received 26 May 2000/Accepted 19 June 2000

Recent evidence suggests that certain LEF/TCF family members act as repressors in the absence of Wnt signaling. We show here that repression by LEF1 requires histone deacetylase (HDAC) activity. Further, LEF1 associates in vivo with HDAC1, and transcription of a model LEF1-dependent target gene is modulated by the ratio of HDAC1 to beta -catenin, implying that repression by LEF1 is mediated by promoter-targeted HDAC. Consistent with this hypothesis, under repression conditions the promoter region of a LEF1 target gene is hypoacetylated. By contrast, when the reporter is activated, its promoter becomes hyperacetylated. Coexpression of beta -catenin with LEF1 and HDAC1 results in the formation of a beta -catenin/HDAC1 complex. Surprisingly, the enzymatic activity of HDAC1 associated with beta -catenin is attenuated. Together, these findings imply that activation of LEF1-dependent genes by beta -catenin involves a two-step mechanism. First, HDAC1 is dissociated from LEF1 and its enzymatic activity is attenuated. This first step yields a promoter that is inactive but poised for activation. Second, once HDAC1-dependent repression has been overridden, beta -catenin binds LEF1 and the beta -catenin-LEF1 complex is competent to activate the expression of downstream target genes.

* Corresponding author. Mailing address: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550. Phone: (801) 581-5597. Fax: (801) 585-1980. E-mail: don.ayer{at}hci.utah.edu.

Molecular and Cellular Biology, September 2000, p. 6882-6890, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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