Polycomb Mediated Chromatin Organization Reveals Transcriptional Silencers Required for Embryonic Development

Polycomb repressive complex 2 (PRC2), a key regulator of metazoan development, induces transcriptional silencing by organizing repressive chromatin structures. To understand PRC2 associated genome topology, we performed chromatin interaction analyses focusing on three core subunits of PRC2 in embryonic stem cells (ESCs). Our comprehensive and high-resolution PRC2 interactome reveals connectivity networks manifested by the extensive looping between distal regulatory elements (DREs) and genes controlling differentiation. The deletion of these non-coding DREs in mice results in transcriptional de-repression and embryonic lethality. While functioning as silencers in ESCs, these DREs can transition into active enhancers during development, suggesting their dual regulatory activities. Integrative analysis of the three dimensional genome organization and spatial clusters of PRC2-chromatin hubs reveals the compact, peripheral assembly as the structural basis of the silencing compartments. Our study uncovers the molecular identity of PRC2 silencers, their associated genome architectures, and offers the exciting possibility of targeted re-activation of epigenetically silenced genes. 1. Chromatin interaction analyses focusing on three core subunits of PRC2 (Eed, Ezh2, Suz12) in embryonic stem cells (ESCs) were performed to understand PRC2 associated genome topology and identify the distal regulatory elements (DREs). 2. Regulation activities of the DREs studied with the deletion of non-coding DREs in mice.