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Abstract
The transcriptional factor Snail1 is a repressor of E-cadherin (CDH1) gene expression essential for triggering epithelial-mesenchymal transition. Snail1 represses CDH1, directly binding its promoter and inducing the synthesis of the Zeb1 repressor. In this article, we show that repression of CDH1 by Snail1, but not by Zeb1, is dependent on the activity of Polycomb repressive complex 2 (PRC2). Embryonic stem (ES) cells null for Suz12, one of the components of PRC2, show higher levels of Cdh1 mRNA than control ES cells. In tumor cells, interference of PRC2 activity prevents the ability of Snail1 to downregulate CDH1 and partially derepresses CDH1. Chromatin immunoprecipitation assays demonstrated that Snail1 increases the binding of Suz12 to the CDH1 promoter and the trimethylation of lysine 27 in histone H3. Moreover, Snail1 interacts with Suz12 and Ezh2, as shown by coimmunoprecipitation experiments. In conclusion, these results demonstrate that Snail1 recruits PRC2 to the CDH1 promoter and requires the activity of this complex to repress E-cadherin expression.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We greatly thank Salvador Aznar-Benitah for the SNAI1-specific siRNA and for helpful discussions and Berta Alsina for her advice. We also thank Marta Garrido and Álvaro Jansà for technical assistance.
This work was supported by Danish National Research Foundation and Danish Medical Research Council grants to K.H. and by grants from the Ministerio de Ciencia y Tecnología (SAF2003-02324 and SAF2006-00339) to A.G.H. Partial support from Instituto Carlos III (RTICCC, C03710) and from the Generalitat de Catalunya (2005SGR00970) is also appreciated. N.H. and M.E were recipients of predoctoral fellowships from the Ministerio de Educación. S.P. was supported by a postdoctoral fellowship from the Ministerio de Educación. V.D. was supported by a La Cierva contract.