A functional analysis of the corepressor Groucho in the development of Drosophila melanogaster

The Drosophila gene groucho ( gro) encodes a transcription factor that functions as a corepressor to mediate long-range silencing. The Groucho (Gro) protein is the prototype for a large family of transcription factors found in most metazoans. As a corepressor, Gro is recruited to silencing elements by DNA-bound transcription factors. Long-range silencing can span multiple enhancers affecting genes several Kb away from the point of recruitment.;Gro interacts directly with the histone deacetylase Rpd3, which enhances Gro-mediated repression. Gro colocalizes with Rpd3 to the chromatin of a target gene and this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.;Gro-mediated long-range silencing plays diverse roles in development and signal transduction. We have used ChIP-Chip analysis in Drosophila embryos and wing imaginal discs to determine the genome-wide occupancy of Gro binding in these developmental contexts. These data have revealed expected target genes known from previous genetic studies, as well as novel target genes. These findings are consistent with the role of Gro as a pleiotropic global regulator, but also suggest that Gro is especially important in the silencing of genes that regulate signaling and transcription.;Gro functions as a point of crosstalk between the Notch and Ras signaling pathways, which have an antagonistic relationship in several developmental contexts. Gro mediates repression of pro-neural genes downstream of Notch signaling. We demonstrate that Gro is directly phosphorylated by MAPK, resulting in decreased Gro-mediated repression. This provides a mechanistic explanation of how Gro can mediate crosstalk between the pathways.