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The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2.

Adam D Longhurst | Kyle Wang | Harsha Garadi Suresh | Mythili Ketavarapu | Henry N Ward | Ian R Jones | Vivek Narayan | Frances V Hundley | Arshia Zernab Hassan | Charles Boone | Chad L Myers | Yin Shen | Vijay Ramani | Brenda J Andrews | David P Toczyski
eLife | 2025

Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.

Pubmed ID: 39903505

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: R01 AG057497
  • Agency: NEI NIH HHS, United States
    Id: R01 EY027789
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM118104
  • Agency: NIDA NIH HHS, United States
    Id: U01 DA052713
  • Agency: Sandler Program for Breakthroughs in Biomedical Research (PBBR),
    Id: UM1HG009402
  • Agency: Sandler Program for Breakthroughs in Biomedical Research (PBBR),
    Id: R01AG057497
  • Agency: Sandler Program for Breakthroughs in Biomedical Research (PBBR),
    Id: R01EY027789
  • Agency: NHGRI NIH HHS, United States
    Id: UM1 HG009402
  • Agency: Sandler Program for Breakthroughs in Biomedical Research (PBBR),
    Id: U01DA052713

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