Gene-specific transcriptional silencing by REST function

项目摘要 RE-1沉默转录因子（REST），也称为神经元限制性沉默因子 NRSF是抑制干细胞和非神经元细胞中神经元基因表达的主调节因子。 REST的过度表达会导致几种类型的脑肿瘤的发生，其调节失调会导致脑肿瘤的发生。 在多种神经系统疾病中被检测到。巨大的差异出现报告不同的基因受 REST控制，这可能是由于REST在不同环境中的剂量和细胞类型依赖性。在这 因此，我们将测试REST转录沉默活性可以由小分子控制的假设。 我们已经开发了REST调节蛋白的抑制剂。特别是，我们将研究细胞毒性 当REST驱动肿瘤生长时，这些抑制剂在胶质母细胞瘤细胞中的作用。此外，我们将了解 在原子水平上，通过定量评估REST的相互作用， 它的DNA靶点和基因沉默的辅助抑制物。从长远来看，我们希望识别小分子 抑制剂来治疗由过度REST活性驱动的疾病。

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.