Abstract

A major unsolved problem in epigenetics is how RNA regulates Polycomb repressive complex 2 (PRC2), a complex that trimethylates histone H3 Lys27 (H3K27me3) to form repressive chromatin. Key questions include how PRC2 binds RNA in vivo and what the functional consequences of binding are. In this Perspective, we expound on the viewpoint that RNA is integral to the stepwise regulation of PRC2 activity. Using the long non-coding RNA XIST and X chromosome inactivation as a model, we discuss evidence indicating that RNA is involved in PRC2 recruitment onto chromatin, in induction of its catalytic activity and in its eviction from chromatin. Studies have also implicated RNA in controlling promoter-proximal pausing of RNA polymerase II. The cumulative data argue that the functional consequences of PRC2-RNA interactions crucially depend on RNA conformation. We recognize that alternative hypotheses exist and therefore we attempt to integrate contrary data. Thus, although an RNA-rich landscape is emerging for Polycomb complexes, additional work is required to resolve a broad range of data interpretations.