8/ We propose that H3K27me3 mimicry has repeatedly emerged through evolution to restrict the spread of Polycomb domains by breaking the PRC2-H3K27me3 positive feedback loop.

7/ We find that the allosteric regulatory activities of JARID2 and PALI1 synergise to antagonise PRC2 during mouse development and restrict the spread of Polycomb domains in mECS.

6/ Unexpectedly, the H3K27me3 mimicry-defective JARID2 K116R exhibited a homeotic transformation characteristics of Polycomb gain-of-function!

This seemingly goes against the prevalent paradigm where JARID2 K116me3 is believed to positively regulate PRC2.

5/ To determine what is the function of H3K27me3 mimicry, we used CRISPR/Cas to generate 3 knock-in mouse lines: each included a single K-to-R mutation that specifically prevents JARID2, PALI1 or PALI2 from mimicking H3K27me3.

4/ Why do JARID2 and PALI1/2 mimic H3K27me3? They are thought to "jump start" PRC2 in the absence of H3K27me3, to initiate H3K27me3 de novo. While this model agrees with biochemical and KO+rescue experiments in cells, it was never tested in vivo.

3/ H3K27me3 binds to PRC2. Some proteins mimic H3K27me3 to directly interact with the H3K27me3-binding site in PRC2.

- The Margueron lab showed it for JARID2: pmc.ncbi.nlm.nih.gov/articles/PMC...
- We showed it for PALI1/2: www.nature.com/articles/s41...

2/ Credit first: Led by Samuel Agious, a PhD student in the @davidovichlab.bsky.social, @monashuniversity.bsky.social, through collaboration with the Eddy McGlinn lab.
www.biorxiv.org/content/10.1...