Competition between PRC2.1 and 2.2 subcomplexes regulates PRC2 chromatin occupancy in human stem cells

Area of Science:

• Epigenetics
• Molecular Biology
• Stem Cell Biology

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for gene silencing in pluripotent stem cells.
• PRC2 functions by methylating histone H3 at lysine 27 (H3K27me3).
• Two distinct PRC2 subcomplexes, PRC2.1 and PRC2.2, exist, differing in their accessory proteins.

Purpose of the Study:

• To investigate the functional differences between PRC2.1 and PRC2.2 subcomplexes.
• To determine how manipulating PRC2 subcomplex formation affects chromatin occupancy and gene expression in human induced pluripotent stem cells (iPSCs).

Main Methods:

• Introduction of separation-of-function mutations in the SUZ12 subunit of PRC2.
• Generation of iPSCs exclusively harboring PRC2.1 or PRC2.2.
• Analysis of PRC2 chromatin occupancy and gene expression patterns.

Main Results:

• PRC2.2 exclusively occupies polycomb target genes at low levels, leading to homeobox transcription factor upregulation.
• Forcing PRC2.1 formation results in drastically increased PRC2 chromatin occupancy.
• Cancer-associated mutations were found to coerce PRC2.1 formation.

Conclusions:

• The ratio of PRC2.1 to PRC2.2 subcomplexes influences PRC2 chromatin occupancy.
• Altering this ratio may play a role in developmental processes and disease, such as cancer.
• Understanding subcomplex dynamics offers insights into epigenetic regulation and its dysregulation.