RNA-induced PRC2 inhibition depends on the sequence of bound RNA

Area of Science:

• Epigenetics
• Molecular Biology
• RNA Biology

Background:

• Polycomb Repressive Complex 2 (PRC2) regulates gene expression via histone H3K27 trimethylation.
• PRC2 activity is modulated by proteins, modifications, and notably, RNA.
• Previous research focused on G-quadruplex (G4) RNAs inhibiting PRC2 activity.

Purpose of the Study:

• To investigate how diverse RNAs, beyond G4 structures, associate with and regulate PRC2.
• To elucidate the molecular mechanisms underlying PRC2-RNA interactions.
• To reconcile conflicting findings regarding PRC2-associated RNAs in vivo.

Main Methods:

• Cryo-electron microscopy (cryo-EM) structural analysis.
• Biochemical assays to assess methyltransferase activity.
• Investigation of RNA structure-PRC2 interactions.
• Analysis of RNA-binding insensitivity to photochemical crosslinking.

Main Results:

• Single-stranded G-rich RNA and pUG-fold structures induce PRC2 dimerization and inhibit activity, similar to G4 RNAs.
• PRC2's flexible arginine-rich loops accommodate various RNA structures, forming conserved interfaces.
• PRC2-RNA interactions are robust and not detected by standard photochemical crosslinking methods.

Conclusions:

• RNA-mediated regulation of PRC2 is not restricted to G4 structures.
• Diverse RNA secondary structures can inactivate PRC2 through dimerization.
• The findings support a broader role for the transcriptome in regulating PRC2 function.