Fig. 6.

Oncohistone-mimic, EZHIP blocks H3K27me3 spreading by inhibiting allosterically-stimulated PRC2. Schematic depicting the molecular mechanism by which EZHIP expression leads to the loss of H3K27me3 spreading. In cells lacking EZHIP expression (in blue), PRC2 is recruited to CpG islands and catalyzes H3K27me3 at recruitment sites. H3K27me3-marked nucleosomes proximal to the recruitment site allosterically activate PRC2 and promote spreading in cis to form broad H3K27me3 domains. Similarly, in cells expressing EZHIP (red), PRC2 is recruited to CpG islands and can catalyze H3K27me3 at proximal nucleosomes due the weaker inhibition potential of EZHIP for unstimulated PRC2. However, spreading of H3K27me3 is blunted due to enhanced binding of EZHIP to allosterically stimulated PRC2. The formation of H3K27me3-PRC2-EZHIP ternary complex inhibits PRC2 spreading and provides a mechanism to explain the formation of narrow H3K27me3 peaks found in PFA ependymomas