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 CML, breast cancer and immortalized cell lines.

细胞周期G1期的推进是细胞分裂过程中调控最为严苛的步骤。本研究采用化学遗传学方法（chemogenetic approach），旨在发掘调控细胞周期进程的全新细胞网络。该策略鉴定得到可改变细胞对G1/S转换抑制剂敏感性的基因功能簇。多梳抑制复合物2（Polycomb Repressor Complex 2, PRC2）组分的突变可逆转由CDK4/6抑制剂帕博西尼（palbociclib）诱导的增殖抑制效应，但对S期或有丝分裂抑制剂无此类逆转作用。除其核心催化亚基外，PRC2.1辅助蛋白MTF2的突变（而非PRC2.2蛋白JARID2）可使细胞对帕博西尼治疗产生耐药性。本研究发现，PRC2.1（MTF2）而非PRC2.2（JARID2），对于全基因组范围及启动子区域CpG岛（CpG islands）处的H3K27me3沉积具有关键调控作用。这一调控效应涵盖CDK4/6细胞周期蛋白CCND1与CCND2启动子内的CpG岛，而MTF2的缺失会导致CCND1与CCND2的表达均上调。本研究结果证实，PRC2.1而非PRC2.2可在多种细胞谱系中拮抗G1期进程，涉及的细胞类型包括慢性髓系白血病（CML）、乳腺癌及永生化细胞系。