Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

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 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 prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173-83. ©2017 AACR.