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 ce...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/97577 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adam D Longhurst |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-21eff5079bed4ec9a35323989d4e8a9b |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-21eff5079bed4ec9a35323989d4e8a9b2025-02-04T16:14:45ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.97577The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2Adam D Longhurst0https://orcid.org/0000-0002-2463-8370Kyle Wang1Harsha Garadi Suresh2Mythili Ketavarapu3Henry N Ward4Ian R Jones5Vivek Narayan6Frances V Hundley7Arshia Zernab Hassan8Charles Boone9Chad L Myers10Yin Shen11Vijay Ramani12Brenda J Andrews13https://orcid.org/0000-0001-6427-6493David P Toczyski14https://orcid.org/0000-0001-5924-0365University of California, San Francisco, San Francisco, United States; Tetrad Graduate Program, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, CanadaGladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesBioinformatics and Computational Biology Graduate Program, University of Minnesota – Twin Cities Minneapolis, Minneapolis, United StatesInstitute for Human Genetics, University of California, San Francisco, San Francisco, United States; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, United StatesInstitute for Human Genetics, University of California, San Francisco, San Francisco, United StatesUniversity of California, San Francisco, San Francisco, United States; Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States; Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, United StatesDepartment of Computer Science and Engineering, University of Minnesota – Twin Cities Minneapolis, Minneapolis, United StatesDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, CanadaBioinformatics and Computational Biology Graduate Program, University of Minnesota – Twin Cities Minneapolis, Minneapolis, United States; Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, United StatesInstitute for Human Genetics, University of California, San Francisco, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United StatesGladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesThe Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, CanadaUniversity of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United StatesProgression 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.https://elifesciences.org/articles/97577molecular biologycell cycleD-type cyclinspalbociclib |
| spellingShingle | 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 The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 eLife molecular biology cell cycle D-type cyclins palbociclib |
| title | The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 |
| title_full | The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 |
| title_fullStr | The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 |
| title_full_unstemmed | The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 |
| title_short | The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2 |
| title_sort | prc2 1 subcomplex opposes g1 progression through regulation of ccnd1 and ccnd2 |
| topic | molecular biology cell cycle D-type cyclins palbociclib |
| url | https://elifesciences.org/articles/97577 |
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