Gene-specific transcriptional silencing by REST function

项目总结 RE-1沉默转录因子(REST)，又称神经元限制性沉默因子 神经再生因子(NRSF)，是抑制干细胞和非神经细胞中神经基因表达的主控调节因子。 REST的过度表达导致几种类型的脑瘤的发生，其调节失调 在多种神经系统疾病中都被检测到。报告的不同基因会产生巨大的差异 REST对照，这可能是由于不同环境中REST的剂量和细胞类型依赖所致。在这 格兰特，我们将测试休息转录沉默活动可以由小分子控制的假设 我们开发的REST调节蛋白的抑制剂。特别是，我们将研究细胞毒性 静息时这些抑制物对胶质母细胞瘤细胞生长的影响。此外，我们将理解 在原子水平上，通过定量评估其相互作用来研究静止作用的分子机制 它的DNA靶标和用于基因沉默的辅助抑制物。从长远来看，我们希望识别出小分子 用于治疗由过度休息活动引起的疾病的抑制剂。

PROJECT SUMMARY The RE-1 silencing transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a master regulator that represses the expression of neuronal genes in stem cell and non-neuronal cells. Overexpression of REST leads to the development of several types of brain tumors, and its dysregulation has been detected in multiple neurological diseases. The huge discrepancy arises reporting different genes subject to REST control, which might be due to the dose- and cell type-dependency of REST in different contexts. In this grant, we will test the hypothesis that REST transcriptional silencing activity can be controlled by small molecule inhibitors of the regulatory protein of REST we have developed. Particularly, we will investigate the cytotoxic effect of these inhibitors in glioblastoma cells when REST drives tumor growth. Furthermore, we will understand at the atomic level the molecular mechanism of REST function through quantitative assessment of its interaction with its DNA targets and its co-repressors for gene silencing. In the long run, we want to identify small molecule inhibitors to treat diseases driven by excess REST activity.