Drosophila Scm self-assembles into PcG bodies to recruit PRC2.1 to target genes during Polycomb silencing initiation

While Polycomb-based gene silencing relies upon the generation of large, condensed domains of histone H3K27 trimethylation, the mechanisms forming and maintaining these domains are incompletely understood. Several previously identified mechanisms concentrate PRC2 and its H3K27me3 activity, including allosteric activation, binding to H2Aub, and concentration into PcG bodies through weak multivalent interactions with other Polycomb group proteins. Here, using the Drosophila nurse cell system to study silencing initiation in developing tissue, we discover a new mechanism. The scaffolding protein Sex comb on midleg (Scm) first polymerizes into PcG bodies independently of PRC1 and PRC2. These Scm-containing bodies then recruit PRC2 through a direct, structured interaction between the Scm–Zf-FCS domain and the Pcl atypical Tudor domain. Finally, we show that the Scm–Zf-FCS/Pcl–Tudor interaction is required for viability and Hox gene regulation during somatic cell development. Our work discovers a new mechanism anchoring PRC2 to PcG bodies that explains how cells can rapidly create and maintain large domains of H3K27me3. It also raises a new possibility that cells could regulate Scm polymerization to determine the size and location of H3K27me3 domains.