Histone methylation by PRC2 is inhibited by active chromatin marks

Chromatin modifiers serve as regulatory switches that control the cell cycle, maintain pluripotency and drive differentiation and development. Positive feedback mechanisms help to pass on transcriptional information from one generation of cells to the next one. The polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 at lysine 27, a typical mark of repressive chromatin. De novo methylation requires sequence-specific recruitment factors. In contrast, propagation and inheritance of the H3K27me3 mark after replication relies on a self-maintaining feedback loop: direct interaction of PRC2 with existing H3K27me3 marks triggers an allosteric stimulation of the methyltransferase activity and results in efficient modification of new histones that have been incorporated in repressive chromatin regions.

In this study we present an inhibitory mechanism that limits the spread of H3K27 methylation and protects active chromatin by breaking the positive feedback loop. PRC2 is allosterically inhibited by nucleosomes carrying active chromatin modifications such as H3K4me3 or H3K36me2/3. The mechanism is conserved in mammals, flies and even plants. In addition plants have distinct PRC2 subcomplexes and can modulate their specificity by the choice of the Su(z)12 homologue. Furthermore, we have identified Nurf55 as another histone binding module in the PRC2 complex that recognizes unmodified histone H3 but not H3K4me3.

Taken together, H3K27 methylation presents itself as a typical bistable switch. It is driven by the positive feedback loop in PRC2 activation and limited by active mark inhibition. Numerous chromatin modifying complexes recognize their own products and positive feedback loops are a common mechanism. We postulate that all these complexes need an additional inhibitory switch that prevents spreading of histone modifications over the entire genome.