Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

摘要

It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19^Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a pre-requisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex is identified containing LSD1, PRC2 and the Notch ternary complex. These findings demonstrate a novel function of Notch and provides further insight into the mechanisms of Notch-mediated tumorigenesis.