Affar El Bachir, Gay Frédérique, Shi Yujiang, Liu Huifei, Huarte Maite, Wu Su, Collins Tucker, Li En, Shi Yang
Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Mol Cell Biol. 2006 May;26(9):3565-81. doi: 10.1128/MCB.26.9.3565-3581.2006.
Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing approximately 75%, approximately 50%, and approximately 25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.
小鼠中阴阳1（YY1）转录因子的组成型缺失导致着床前致死。在本研究中，我们利用同源重组技术生成了携带表达不同量YY1的yy1等位基因的基因敲除小鼠。对表达约75%、约50%和约25%正常YY1量的yy1突变胚胎进行表型分析，确定了胚胎发育后期YY1存在剂量依赖性需求。事实上，YY1水平的降低以剂量依赖的方式损害胚胎生长和活力。对相应的小鼠胚胎成纤维细胞的分析还揭示了YY1剂量与细胞增殖之间的紧密相关性，YY1的完全缺失会导致胞质分裂失败和细胞周期停滞。同样，RNA干扰介导的HeLa细胞中YY1的抑制可阻止胞质分裂，导致增殖停滞，并增加细胞对各种凋亡剂的敏感性。全基因组表达谱分析确定了大量与细胞生长、增殖、胞质分裂、凋亡、发育和分化相关的YY1靶基因，这表明YY1通过复杂的转录网络协调多个重要的生物学过程。这些数据不仅为YY1的发育作用和细胞功能的分子基础提供了新的线索，也为控制真核细胞增殖、凋亡和分化的一般机制提供了见解。
