Thanks to the perseverence of Egor Pavlenko and Paul Sauer in particular, we have now published this work in Molecular Cell: https://doi.org/10.1016/j.molcel.2024.08.025
We've got a lot of help from Linda Zirden and Juliane Renn from our lab, but also the groups of Karissa Sanbonmatsu, Robert Hänsel-Hertsch and Farnusch Kaschani. This work was supported by the fantastic SFB1430 (https://www.uni-due.de/crc1430/) and the CANTAR network, for which we are very grateful!
Using #cryoEM, we found the chromatin regulator complex PRC2 to form dimers on chromatin. PRC2 dimerization had been shown before, e.g. by the Cech, Armache, Liu (UT Southwestern), and Kasinath Labs. However, the arrangement that we found is different in that one PRC2 complex serves as an allosteric activator for the other. As a substrate of its own methyltransferase activity, PRC2 auto-methylates a flexible loop (am-loop). We show that the trimethylated K510 of that loop utilizes the known binding site of the regulatory subunit EED of the partner PRC2 for its stimulation. This bypasses the need of other allosteric activators that are known to be required for efficient H3K27 trimethylation by PRC2. Our work provides an explanation for the stimulatory effect of PRC2 auto-methylation reported before, and showcases and intriguing regulatory mechanism caused by enzymatic self-targeting. It reinforces the central role of EED for PRC2 function. Allosteric activation by dimerization adds another layer of complexity to the diverse ways in which PRC2 is able to integrate regulatory cues from its chromatin environment. It will take many more studies to fully understand the implications of this context dependent function!