The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2

Area of Science:

• Cell Biology
• Molecular Biology
• Epigenetics

Background:

• Cell cycle progression, particularly the G1 phase, is tightly regulated.
• Identifying novel regulators of cell cycle progression is crucial for understanding cellular division and developing targeted therapies.

Purpose of the Study:

• To discover novel cellular networks regulating cell cycle progression using a chemogenetic approach.
• To investigate the role of Polycomb Repressive Complex 2 (PRC2) components in cell cycle regulation and response to CDK4/6 inhibitors.

Main Methods:

• Chemogenetic screening to identify genes affecting sensitivity to G1/S transition inhibitors.
• Mutation analysis of Polycomb Repressive Complex 2 (PRC2) components, including MTF2 and JARID2.
• Assessment of H3K27me3 deposition and gene expression of CCND1 and CCND2.

Main Results:

• Components of PRC2 rescued proliferation inhibition by the CDK4/6 inhibitor palbociclib.
• Mutation of the PRC2.1 accessory protein MTF2, but not PRC2.2 protein JARID2, conferred resistance to palbociclib.
• MTF2, but not JARID2, was essential for H3K27me3 deposition at CpG islands, including promoters of CCND1 and CCND2, leading to their upregulation upon MTF2 loss.

Conclusions:

• PRC2.1, specifically MTF2, plays a critical role in antagonizing G1 phase progression across various cell lineages.
• MTF2's function in H3K27me3 deposition is key to its role in regulating cell cycle and sensitivity to CDK4/6 inhibitors.
• These findings highlight PRC2.1 as a potential therapeutic target for enhancing the efficacy of CDK4/6 inhibitors in cancers like CML and breast cancer.