JARID2 and AEBP2 regulate PRC2 activity in the presence of H2A ubiquitination or other histone modifications
The Polycomb repressive complexes PRC1 and PRC2 functionally interact to coordinate cell type identity by the epigenetic regulation of gene expression. It has been proposed that PRC2 is recruited to genomic loci via the recognition of PRC1-mediated mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1), but the mechanism of this process remains poorly understood. Here, we report the cryo-EM structure of human PRC2 with cofactors JARID2 and AEBP2 bound to a nucleosome substrate containing H2AK119ub1. We find that JARID2 and AEBP2 each interact with one of the two ubiquitin molecules in the nucleosome. A ubiquitin-interaction motif (UIM) in JARID2 is sandwiched between ubiquitin and the histone H2A-H2B acidic patch. Simultaneously, the tandem zinc-fingers of AEBP2 interact with the second ubiquitin and the histone H2A-H2B surface on the opposite side of the nucleosome. JARID2 plays a dual role in the H2AK119ub1 dependent stimulation of PRC2 through interactions with both EED via its K116 trimethylation and with the H2AK119-ubiquitin. AEBP2, on the other hand, appears to primarily serve as a scaffold contributing to the interaction between PRC2 and the H2AK119ub1 nucleosome. Our structure also provides a detailed visualization of the EZH2-nucleosome interface, revealing a segment of EZH2 (named "bridge helix") that is stabilized as it bridges the EZH2(SET) domain, the H3 tail and the nucleosomal DNA. In addition to the role played by AEBP2 and JARID2 in PRC2 regulation by H2AK119ub1 recognition, we also observe that the presence of these cofactors partially overcomes the inhibitory effect that H3K4- and H3K36- trimethylation have on core PRC2. Together, our results reveal the central role played by cofactors JARID2 and AEBP2 in orchestrating the crosstalk between histone post-translational modifications and PRC2 methyltransferase activity. ### Competing Interest Statement The authors have declared no competing interest.
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