Nascent RNA interaction keeps PRC2 activity poised and in check

Area of Science:

• Epigenetics and Gene Regulation
• Molecular Biology
• Chromatin Biology

Background:

• Polycomb-repressive complex 2 (PRC2) establishes repressive chromatin marks, specifically histone H3 Lys27 di- and tri-methylation (H3K27me2/3).
• PRC2, via its EZH2 subunit, interacts with nascent RNA transcripts from active genes, even those lacking H3K27me2/3 marks.

Purpose of the Study:

• To investigate the functional consequence of PRC2 interaction with nascent RNA.
• To determine if nascent RNA binding regulates PRC2 activity in vivo.

Main Methods:

• Biochemical assays to assess the effect of RNA on PRC2 activity in vitro.
• CRISPR-mediated gene editing to truncate PRC2-interacting nascent RNA in embryonic stem cells.

Main Results:

• In vitro biochemical analyses demonstrated that RNA binding nonspecifically inhibits SET domain-containing proteins, including PRC2.
• CRISPR-mediated truncation of a specific nascent RNA rescued PRC2-dependent H3K27me2/3 deposition.
• These findings suggest nascent RNA interaction negatively regulates PRC2 activity.

Conclusions:

• Nascent RNA binding acts as an inhibitory mechanism for PRC2.
• This regulation supports a model where PRC2 activity is restricted to genes already silenced by transcriptional repressors.