beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator

Recent evidence suggests that certain LEF/TCF family members act as repress ors in the absence of Wnt signaling. We show here that repression by LEF1 r equires histone deacetylase (HDAC) activity. Further, LEF1 associates in vi vo with HDAC1, and transcription of a model LEF1-dependent target gene is m odulated by the ratio of HDAC1 to beta-catenin, implying that repression by LEF1 is mediated by promoter-targeted HDAC. Consistent with this hypothesi s, 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 r esults in the formation of a beta-catenin/HDAC1 complex. Surprisingly, the enzymatic activity of HDAC1 associated with beta-catenin is attenuated. Tog ether, these findings imply that activation of LEF1-dependent genes by beta -catenin involves a two-step mechanism. First, HDAC1 is dissociated from LE F1 and its enzymatic activity is attenuated. This first step yields a promo ter that is inactive but poised for activation. Second, once HDAC1-dependen t repression has been overridden, beta-catenin binds LEF1 and the beta-cate nin-LEF1 complex is competent to activate the expression of downstream targ et genes.