Forkhead proteins control the outcome of transcription factor binding by antiactivation

Transcription factors with identical DNA-binding specificity often activate different genes in vivo. Yeast Ace2 and Swi5 are such activators, with targets we classify as Swi5-only, Ace2-only, or both. We define two unique regulatory modes. Ace2 and Swi5 both bind in vitro to Swi5-only genes such as HO, but only Swi5 binds and activates in vivo. In contrast, Ace2 and Swi5 both bind in vivo to Ace2-only genes, such as CTS1, but promoter-bound Swi5 fails to activate. We show that activation by Swi5 is prevented by the binding of the Forkhead factors Fkh1 and Fkh2, which recruit the Rpd3(Large) histone deacetylase complex to the CTS1 promoter. Global analysis shows that all Ace2-only genes are bound by both Ace2 and Swi5, and also by Fkh1/2. Genes normally activated by either Ace2 or Swi5 can be converted to Ace2-only genes by the insertion of Fkh-binding sites. Thus Fkh proteins, which function initially to activate SWI5 and ACE2, subsequently function as Swi5-specific antiactivators

Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans

In Caenorhaditis elegans, numerous 'synMuv' (synthetic multivulval) genes encode for chromatin-associated proteins involved in transcriptional repression, including an orthologue of Rb and components of the NuRD histone deacetylase complex. These genes antagonize Ras signalling to prevent erroneous adoption of vulval fate. To identify new components of this mechanism, we performed a genome-wide RNA interference (RNAi) screen. After RNAi of 16 757 genes, we found nine new synMuv genes. Based on predicted functions and genetic epistasis experiments, we propose that at least four post-translational modifications converge to inhibit Ras-stimulated vulval development: sumoylation, histone tail deacetylation, methylation, and acetylation. In addition, we demonstrate a novel role for sumoylation in inhibiting LIN-12/Notch signalling in the vulva. We further show that many of the synMuv genes are involved in gene regulation outside the vulva, negatively regulating the expression of the Delta homologue lag-2. As most of the genes identified in this screen are conserved in humans, we suggest that similar interactions may be relevant in mammals for control of Ras and Notch signalling, crosstalk between these pathways, and cell proliferation