Epigenetic regulation by p300: contributonof p300 to overall histone acetylation in vivo, and influence of p300-mediated histone acetylation on other histone modifications

正常水平的组蛋白乙酰化是由两类酶——组蛋白去乙酰化酶和组蛋白乙酰转移酶——的相反作用维持的。这两种酶的活性失衡会导致疾病。因此，组蛋白去乙酰化酶的药理学抑制剂已成为各种疾病的表观遗传治疗的有希望的药物。然而，个体酶对体内整体组蛋白乙酰化的相对贡献尚不清楚。p300蛋白是哺乳动物中已知的超过15种具有组蛋白乙酰转移酶（AT）活性的蛋白之一，并作为大量转录因子的转录共调节因子。我们之前的研究表明，小鼠b细胞中p300 at活性的特异性降低会影响成熟b细胞的基因表达和功能，最终引发致命的自身免疫性疾病。我们建议使用特异性缺乏p300 at活性的原代和永生b细胞来解决p300在体内整体组蛋白乙酰化中的作用。此外，我们将分析p300介导的组蛋白乙酰化如何影响其他组蛋白修饰。

Normal levels of histone acetylation are maintained by the opposing action of two classes of enzymes, histone deacetylases and histone acetyltransferases. An imbalance of these two enzymatic activities can cause disease. Consequently, pharmacological inhibitors of histone deacetylases have emerged as promising drugs for the epigenetic therapy of various diseases. Yet, the relative contribution of individual enzymes to overall histone acetylation in vivo is unknown.The p300 protein is one of more than 15 proteins with histone acetyltransferase (AT) activity known in mammals and acts as a transcriptional co-regulator for a large number of transcription factors. We have previously shown that a reduction of p300 AT-activity specifically in B-cells of mice affects gene expression and function of mature B-cells, eventually triggering a fatal autoimmune disease. We propose to use primary and immortal B-cells specifically lacking p300 AT-activity to address the role of p300 in overall histone acetylation in vivo. In addition, we will analyse how p300-mediated histone acetylation influences other histone modifications.