Structures of PRC2 with its cofactors suggest context-dependent activation affected by cofactor binding.
Major finding: Structures of PRC2 with its cofactors suggest context-dependent activation affected by cofactor binding.
Approach: Cryo-EM structures of PRC2 in complex with its cofactors AEBP2 and JARID2 reveal multiple active conformations.
Impact: JARID2 and AEBP2 may allow PRC2 activation in chromatin environments lacking activating histone marks.
The polycomb repressive complex 2 (PRC2) establishes H3K27 methylation to maintain heterochromatin and promote a transcriptionally repressive state, and PRC2 subunits are subject to mutations and misregulation in cancer. The core PRC2 complex is comprised of four proteins, the catalytic subunit EZH2, EED, SUZ12, and RBAP46/RBAP48. Cofactors such as AEBP2 and JARID2 are found to associate with the complex in vivo. However, the effect of these cofactors on the structure and activity of PRC2 has not been fully elucidated, prompting Kasinath, Faini, Poepsel, and colleagues to obtain high-resolution cryo-EM structures of PRC2 in complex with AEBP2 and JARID2. Two PRC2–AEBP2–JARID2 structures were obtained (at 3.5Å and 3.9Å) in different active conformations, termed the “compact active” and “extended active” states, both with methylated JARID2 bound to EED. In the absence of JARID2 containing K116, PRC2 adopted an inactive conformation termed the “extended basal state.” Two JARID2 molecules bound simultaneously to PRC2 in the allosteric and active sites, supporting a model in which PRC2 methylates JARID2 at K116, resulting in methylated JARID2 binding to the allosteric site to promote PRC2 activity. The multiple conformational states along with the presence of large disordered regions in AEBP2 and JARID2 suggest an intrinsic conformational variability that may allow PRC2 to integrate diverse biological cues to regulate its activity in different contexts. JARID2 K116me2/3 binding mimicked histone H3 tails and is therefore able to stimulate PRC2 activity in the absence of H3K27me3. Similarly, AEBP2 mimicked unmethylated H3K4 binding to RBAP48, which may affect PRC2 activity in the presence of the inhibitory H3K4me3 mark. Further, AEBP2 established a structural bridge between RBAP48 and the EZH2 SET domain. Altogether, these findings suggest a structural mechanism by which JARID2 and AEBP2 can synergistically activate PRC2, and that by mimicking histone tails, JARID2 and AEBP2 may be able to stimulate PRC2 activity in diverse chromatin environments.
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