Epigenetic Mechanisms of Groucho/Grg/TLE Mediated Transcriptional Repression

The repression of transcription, through the concerted actions of tissue specific DNA binding proteins, Polycomb repressor complexes, and DNA methylation, is essential for maintaining stem cell pluripotency and for cell fate specification in development. In this report, we show that recruitment of the co-repressor protein Grg4 to a Pax DNA-binding site displaces the adaptor protein PTIP and a histone H3K4me complex. Grg4 recruits the arginine methyltransferase PRMT5 to chromatin resulting in symmetric H4R3 dimethylation. PRMT5 is essential for recruiting Polycomb proteins, in a Pax2/Grg4 dependent manner, which results in H3K27 methylation. These data define the early epigenetic events in response to Pax/Grg mediated gene repression and demonstrate that a single DNA binding protein can recruit either an activator or a repressor complex depending on the availability of Grg4. These data suggest a model for understanding the initiation of Groucho/Grg/TLE mediated gene silencing. ► Expression of Grg4 displaces PTIP and Mll3/4 on chromatin at a Pax2 binding site ► Grg4 recruits the PRMT5 arginine methyltransferase to symmetrically methylate H4R3 ► PRMT5 is necessary for PRC2 recruitment and H3K27 methylation ► Grg4 switches the epigenetic marks at a Pax2 target from activating to silencing.