Drosophila Ebi mediates Snail-dependent transcriptional repression through HDAC3-induced histone deacetylation

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Abstract
The Drosophila Snail protein is a transcriptional repressor that is necessary for mesoderm formation. Here, we identify the Ebi protein as an essential Snail co‐repressor. In ebi mutant embryos, Snail target genes are derepressed in the presumptive mesoderm. Ebi and Snail interact both genetically and physically. We identify a Snail domain that is sufficient for Ebi binding, and which functions independently of another Snail co‐repressor, Drosophila CtBP. This Ebi interaction domain is conserved among all insect Snail‐related proteins, is a potent repression domain and is required for Snail function in transgenic embryos. In mammalian cells, the Ebi homologue TBL1 is part of the NCoR/SMRT–HDAC3 (histone deacetylase 3) co‐repressor complex. We found that Ebi interacts with Drosophila HDAC3, and that HDAC3 knockdown or addition of a HDAC inhibitor impairs Snail‐mediated repression in cells. In the early embryo, Ebi is recruited to a Snail target gene in a Snail‐dependent manner, which coincides with histone hypoacetylation. Our results demonstrate that Snail requires the combined activities of Ebi and CtBP, and indicate that histone deacetylation is a repression mechanism in early Drosophila development.