Distinct PRC2 subunits regulate maintenance and establishment of Polycomb repression during differentiation

Area of Science:

• Epigenetics
• Developmental Biology
• Molecular Biology

Background:

• Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator.
• PRC2 deposits histone H3 lysine 27 trimethylation (H3K27me3), a mark of gene silencing.
• PRC2 exists as two distinct holocomplexes, PRC2.1 and PRC2.2, with incompletely understood differential functions.

Purpose of the Study:

• To investigate the distinct roles of PRC2.1 and PRC2.2 during embryonic stem cell (ESC) differentiation into neural progenitor cells (NPCs).
• To elucidate the specific contributions of PRC2 subunits MTF2 (PRC2.1) and JARID2 (PRC2.2) to epigenetic gene regulation during differentiation.

Main Methods:

• Utilized auxin-inducible degradation to specifically deplete MTF2 or JARID2 in differentiating ESCs.
• Analyzed differentiation efficiency and gene expression profiles following subunit depletion.
• Assessed H3K27me3 modification patterns on target genes.

Main Results:

• Depletion of either MTF2 or JARID2 led to incomplete ESC to NPC differentiation.
• Distinct sets of Polycomb target genes were derepressed upon MTF2 or JARID2 loss.
• MTF2 depletion affected genes already marked by H3K27me3, while JARID2 depletion impacted genes undergoing new repression.

Conclusions:

• MTF2 and JARID2 contribute non-redundantly to Polycomb-mediated gene silencing.
• PRC2.1 and PRC2.2 possess distinct functions: PRC2.1 (MTF2) is involved in maintaining repression, while PRC2.2 (JARID2) is crucial for establishing repression during differentiation.