Research on Gene Expression Network via histone acetylation

ski基因最初被认为是一种致癌基因。我们已经证明c-ski原癌基因产物（c-Ski）直接与辅阻遏物N-CoR和mSin 3A结合，并与组蛋白去乙酰化酶（HDAC）形成复合物。c-Ski作为一种辅助抑制因子，是肿瘤抑制因子Mad和Rb以及核激素受体介导的转录抑制所必需的。我们已经产生了缺失sno（ski-related novel）基因的突变小鼠，该基因编码ski相关基因。Sno对于早期发育中的胚泡形成是必需的，sno缺乏的胚胎在发育的早期阶段死亡。sno杂合突变体看起来是健康的，但在它们身上观察到自发产生的肿瘤。此外，当它们被化学致癌物DMBA处理时，它们对肿瘤发生的易感性增加。这些结果表明，ski和sno基因作为癌基因或肿瘤抑制基因取决于细胞环境。我们还产生了缺乏CBP的突变小鼠，CBP是最著名的含有组蛋白乙酰化酶活性的共激活剂。CBP缺陷胚胎在E12.5-E14.5由于脑出血而死亡。出血是由血管形成受损引起的，表明CBP对血管形成的重要作用。Cbp缺陷的胚胎也表现出胎肝造血功能的部分受损。我们发现CBP直接乙酰化c-Myb，c-Myb的乙酰化增强了c-Myb与CBP的结合，这是共激活因子CBP调控转录因子活性的一个有趣的新机制。

The ski gene was originally identified as an oncogene. We have demonstrated that c-ski proto-oncogene product (c-Ski) directly associates with co-repressors N-CoR and mSin3A and forms a complex with histone deacetylase (HDAC). c-Ski acts as a co-repressor, and is required for transcriptional repression mediated by tumor suppressors, Mad and Rb, and nuclear hormone receptors . We have generated the mutant mice lacking the sno (ski-related novel) gene, which encodes the ski-related gene. Sno is essential for blastocyst formation in early development, and the sno-deficient embryos die at an early stage of development. The sno heterozygous mutants appeared to be healthy, but spontaneously arisen tumors were observed in them. Furthermore, they have the increased susceptibility to tumorigenesis when they were treated with the chemical carcinogen DMBA.Similar results were also obtained with the ski heterozygous mutant mice. These results indicate that ski and sno genes act as either oncogene or tumor suppressor depending on the cellular context. We also generated the mutant mice lacking CBP, which is the most famous co-activator containing the histone acetylase activity. The Cbp-deficient embryos died at E12.5-E14.5 due to hemorrhage in the brain. Hemorrhage was caused by impaired formation of blood vessel, indicating the important role of CBP for blood vessel formation. The Cbp-deficient embryos also exhibited the partially impaired hematopoesis in fetal liver. We have found that CBP directly acetylates c-Myb, and acetylation of c-Myb enhances the association between c-Myb and CBP.This is an interesting novel mechanism by which co-activator CBP regulates the activity of transcription factor.