A functional interaction between the histone deacetylase Rpd3 and the corepressor Groucho in Drosophila development

Abstract

The Drosophila gene groucho (gro) encodes a transcriptional corepressor that has critical roles in many development processes. In an effort to illuminate the mechanism of Gro-mediated repression, we have employed Gro as an affinity reagent to purify Gro-binding proteins from embryonic nuclear extracts. One of these proteins was found to be the histone deacetylase Rpd3. Protein-protein interaction assays suggest that Gro and Rpd3 form a complex in vivo and that they interact directly via the glycine/proline rich (GP) domain in Gro. Cell culture assays demonstrate that Rpd3 potentiates repression by the GP domain. Furthermore, experiments employing a histone deacetylase inhibitor, as well as a catalytically inactive form of Rpd3, imply that histone deacetylase activity is required for efficient Gro-mediated repression. Finally, mutations in gro and rpd3 have synergistic effects on embryonic lethality and pattern formation. These findings support the view that Gro mediates repression, at least in part, by the direct recruitment of the histone deacetylase Rpd3 to the template, where it can modulate local chromatin structure. They also provide evidence for a specific role of Rpd3 in early development.

Wnt signaling in disease and in development

“…In the absence of the Wnt signal, TCF acts as a repressor of Wnt/Wg target genes [23], by forming a complex with Groucho [24]. The repressing effect of Groucho is mediated by interactions with Histone Deacetylases (HDAC), which are thought to make DNA refractive to transcriptional activation [25].…”

Wnt signaling and skeletal development

“…In the absence of Wnt signal, TCF acts as a repressor of Wnt target genes by forming a complex with Groucho [10,11]. Groucho interacts with histone deacetylases (HDAC), which are thought to make DNA refractive to transcriptional activation [12]. Once in the nucleus, it is thought that β-catenin can displace Groucho from TCF/LEF resulting in the recruitment of the histone acetylase CBP/ p300 (cyclic AMP response element-binding protein) to activate Wnt target gene transcription [13; Figure 1].…”

Crosstalk between the EGFR and other signalling pathways at the level of the global transcriptional corepressor Groucho/TLE

“…Clearly, homo-oligomerisation is a prerequisite for Gro/TLE repressor activity and, further, Gro/TLEs physically bind both histones and histone deacetylases (specifically, Rpd3/HDAC1) (e.g. Chen et al, 1999;Song et al, 2004). Collectively, these observations have led to the following model: Gro is initially tethered to specific gene regulatory regions via its associations with distinct DNA-bound repressors.…”