Structural basis for inactivation of PRC2 by G-quadruplex RNA.

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator.
• PRC2 silences genes via histone H3 lysine 27 trimethylation.
• PRC2 interacts with RNA, particularly G-quadruplex structures.

Purpose of the Study:

• To elucidate the structural basis of PRC2 interaction with G-quadruplex RNA.
• To understand how RNA binding regulates PRC2 activity.
• To identify functional implications of RNA-mediated PRC2 modulation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at 3.3-Å resolution.
• Biochemical assays to study protein-RNA interactions.
• Zebrafish model for functional validation of mutations.

Main Results:

• Determined the cryo-EM structure of PRC2 bound to G-quadruplex RNA.
• RNA binding induces PRC2 dimerization via EZH2 subunits, inhibiting DNA binding.
• Identified an RNA-binding loop in EZH2 crucial for RNA-DNA exchange and PRC2 regulation.
• A gain-of-function mutation in this loop activates PRC2 in zebrafish.

Conclusions:

• RNA binding is a critical regulator of PRC2 activity and localization.
• PRC2 dimerization induced by RNA blocks access to nucleosomal DNA.
• Structural insights reveal novel mechanisms of epigenetic enzyme regulation by RNA.