The Polycomb repressive complex 2 (PRC2) is a histone methyltransferase complex that is essential for the maintenance of cell identity. PRC2 maintains the repressed state of developmentally-expressed genes by the trimethylation of histone H3 at lysine 27 (H3K27me3). A fully assembled PRC2 complex — holo-PRC2 — comprises of four core subunits, and one or two accessory subunits that regulate its enzymatic and chromatin binding activities. PRC2 binds and represses genes in a subset of CpG islands but the mechanism of targeting to specific loci is not known. The polycomblike (PCL) proteins are PRC2 accessory subunits that bind modified histones, RNA and DNA, and are required to direct PRC2 and H3K27me3 to target loci. Mechanistic studies using holo-PRC2 complexes are challenging and studies that used truncated PCL proteins to determine how they bind DNA have resulted in contradictory findings.
Through quantitative DNA-binding and histone methyltransferase assays, we show that PCL proteins enhance the DNA binding and histone methyltransferase activity of holo-PRC2, in agreement with previous studies. Yet, the affinity of the PRC2-PCL complexes for DNA is driven primarily by electrostatic interactions, rather than a DNA sequence motif. Mutations in recombinant PRC2-PCL complexes uncover the mechanism of DNA binding and decouple it from allosteric stimulation of enzymatic activity. PCL proteins increase the affinity of PRC2 to RNA, allowing RNA to compete with DNA for binding to the PRC2-PCL complex, as shown for other PRC2 complexes. These findings support a model where PCL proteins recruit PRC2 to regions of exposed DNA with low transcriptional activity, without a direct dependency on DNA sequences.