RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2

Area of Science:

• Epigenetics and Gene Regulation
• Molecular Biology
• Chromatin Biology

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for maintaining cell identity by regulating gene expression through histone methylation.
• PRC2 exists in different holo-complexes (PRC2.1 and PRC2.2) with varying accessory subunits.
• The mechanism of RNA-mediated inhibition of PRC2's enzymatic activity is not well understood.

Purpose of the Study:

• To elucidate the mechanism of RNA-mediated inhibition of holo-PRC2 complexes.
• To identify the RNA-binding sites on PRC2.
• To understand how RNA and allosteric activators interact to regulate PRC2 activity.

Main Methods:

• In vivo and in vitro protein-RNA interaction mapping.
• Biochemical assays to study allosteric regulation.
• Comparative analysis of human and mouse PRC2 complexes.

Main Results:

• An RNA-binding patch was identified on the allosteric regulatory site of human and mouse PRC2, near the methyltransferase center.
• RNA binding inhibits holo-PRC2 activity.
• Allosteric activation by H3K27me3 and JARID2-K116me3 peptides relieves RNA-mediated inhibition.
• Both holo-PRC2.1 and holo-PRC2.2 complexes bind RNA.

Conclusions:

• A unified model explains the antagonistic regulation of PRC2 enzymatic activity by RNA and allosteric stimuli.
• The findings provide insights into how different PRC2 holo-complexes are regulated in response to cellular signals.
• This study clarifies the role of RNA in modulating PRC2 function during development and differentiation.