Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin

Area of Science:

• Biochemistry
• Epigenetics
• Cancer Biology

Background:

• Polycomb Repressive Complex 2 (PRC2) is a key epigenetic regulator and a therapeutic target in oncology.
• PRC2 activity is modulated by a positive feedback loop involving its product, H3K27me3, and the EED subunit.
• Mutations in PRC2 subunits (EZH2, EED) are implicated in cancers and Weaver syndrome.

Purpose of the Study:

• To elucidate the stepwise feedback mechanism regulating PRC2 activity.
• To investigate the functional consequences of cancer-associated PRC2 mutations.
• To identify therapeutic strategies targeting PRC2-addicted cancers.

Main Methods:

• Site-directed mutagenesis of EZH2 and EED.
• In vivo activity assays for mutant PRC2 complexes.
• Chromatin immunoprecipitation to assess PRC2 recruitment.
• Genetic and chemical inhibition of PRC2 allosteric activation.

Main Results:

• Mutant PRC2 complexes showed reduced enzymatic activity but maintained chromatin association.
• A stepwise feedback mechanism involving specific residues in EZH2/EED was identified.
• Targeting allosteric activation effectively counteracted oncogenic PRC2 mutations (e.g., EZH2^Y646X).

Conclusions:

• The study reveals a critical regulatory mechanism for PRC2 activity.
• PRC2 activity and chromatin recruitment can be uncoupled.
• Targeting PRC2 allosteric activation presents a promising therapeutic strategy for cancers dependent on PRC2.