Accessory subunits of PRC2 mimic H3K27me3 to restrict the spread of Polycomb domains

The Polycomb repressive complex 2 (PRC2) is essential for normal development by maintaining developmental gene repression. PRC2 deposits the repressive chromatin mark H3 lysine 27 tri-methyl (H3K27me3) through a read-write loop that involves direct interactions between PRC2 and H3K27me3. According to current models, the PRC2-H3K27me3 read-write loop is initiated by the PRC2 subunits JARID2 and PALI1 that mimic H3K27me3. However, it is unknown what restricts the PRC2-H3K27me3 read-write loop from spreading H3K27me3 indefinitely. To answer this question, we generated mutant mice where PRC2 subunits cannot mimic H3K27me3. Unexpectedly, the mutations led to delayed Hox gene activation and a homeotic transformation characteristic of a Polycomb gain of function in vivo and the spread of H3K27me3 beyond Polycomb domains in stem cells. Collectively, we show that H3K27me3 mimicry evolved to compete against the PRC2-H3K27me3 read-write loop in a process that restrains PRC2 and restricts the spread of Polycomb domains. • H3K27me3 mimicry antagonizes Polycomb function in vivo • JARID2 and PALI1 synergize to allosterically regulate PRC2 during development • H3K27me3 mimicry by JARID2 and PALI1 antagonizes PRC2 in stem cells • JARID2 and PALI1 mimic H3K27me3 to restrict the spread of Polycomb domains Some proteins mimic the repressive mark H3K27me3, but the physiological relevance of this phenomenon was unclear. Agius et al. show that the PRC2 subunits JARID2 and PALI1 mimic H3K27me3 to antagonize PRC2-mediated H3K27me3 deposition, limit Polycomb domain spreading, and enable timely activation of developmental genes in vivo .