Ebi alleviates excessive growth signaling through multiple epigenetic functions in Drosophila

Abstract

As multicellular organisms develop, many cells permanently stop dividing and undergo terminal differentiation. The G1 phase of the cell cycle is thought to be the critical decision point for differentiation. Many growth factors, such as epidermal growth factor, are involved in regulating the G1 to S phase transition, and aberrant activation of growth factor signaling is one of the critical causes of tumor formation. Therefore, each cell must have proper mechanisms to suppress inappropriate/excessive activation of growth factor signaling, but the underlying molecular mechanisms remain undefined. Here, we found that ebi, a Drosophila homologue of genes encoding transducin-b-like 1 and transducin-b-like 1-related protein, mitigated excess growth stimulation by taking advantage of its distinct epigenetic functions. Ebi acted as a corepressor of transcription by forming a complex with retinoblastoma family protein (RBF), a Drosophila homologue of retinoblastoma, and regulating the expression of specific target genes of the Rbf/E2F pathway. Furthermore, ebi also sustained expression of certain genes, including Rbf, encoding factors that inhibit progression out of G1. Our genetic studies suggest that the antagonistic function of ebi against the Polycomb group silencing complex plays a role in the G1/S phase transition.

Hunting complex differential gene interaction patterns across molecular contexts

“…Importantly, the 14 gene interactions shared by E2F and Cbt (green nodes in Figure 5b) were conspicuous within this group, suggesting a potential coherent core network modulated to promote proliferation (Supplementary Results). Interestingly, our analysis revealed novel interactions that suggest a role for RIO kinases in modulating the function of a transcriptional repressor Ebi, on cell cycle genes (29). We also uncovered several negative cell cycle regulatory loops predicted to limit proliferation that are uniquely engaged when E2F is activated, but not when Cbt is activated.…”

Regulatory system for the G1‐arrest during neuronal development in Drosophila

“…Inhibition of Psc, one of the major components of PcG, alleviates the reduction of Rbf and rux expression in ebi mutant (Lim et al . ) (Fig. A).…”

“…This supports the idea that ebi may act at G1-S in many situations. In terms of cell cycle regulation, recent biochemical analysis revealed that Ebi is forming a complex with RBF1 and inhibits the expression of target genes Rbf/dE2F1 pathway (Lim et al 2013). However, Ebi did not seem to associate with L(3)mbt, suggesting that Ebi/RBF/ E2F is a distinct complex to the dREAM/MMB complex acting in the G1 phase.…”

“…; Lim et al . ). Given the fact that Rbf and rux are directly silenced by PcG, ebi might regulate expression of those cell cycle inhibitors by modulating activity of PcG (Fig.…”

“…Notch activation can induce SMW by supporting expression of cycA , and recent studies revealed that Dl is prolonged around the MF in Elp mutation (Baonza & Freeman ; Lim et al . ).…”