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

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.

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Publication Details

Journal
eLife
Published
2025-02-04
DOI
https://doi.org/10.7554/elife.97577.3
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Chad L. Myers, Charles Boone, David Paul Toczyski, Adam D Longhurst et al.
eLife
Epigenetics and DNA Methylation
article

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

Chad L. Myers, Charles Boone, David Paul Toczyski, Adam D Longhurst, Brenda Andrews, Kyle Wang, Harsha Garadi Suresh, Vijay Ramani, Mythili Ketavarapu, Ian Jones, Henry N. Ward, Vivek Narayan, Frances V Hundley, Arshia Zernab Hassan, Yin Shen
article en

Abstract

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.

eLifeVol. 13
University of Minnesota (US), Gladstone Institutes (US), Harvard University (US), University of California, San Francisco (US), University of Toronto (CA), Twin Cities Orthopedics (US), Cellular Research (United States) (US)
NIH Office of the Director
Openalex Percentile: Top 98%
Epigenetics and DNA Methylation
DOIOpen Access PDFOpenAlex
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