Modular design of synthetic transcriptional regulators

所有的命运都由一组基因决定，这些基因在发育过程中以编程的方式表达 和细胞分化。通常，在糖尿病和癌症等各种疾病中，故障 转录调节器产生基因表达的异常模式，这是疾病的核心。 调控蛋白如何找到它们的结合部位并调节它们的目标基因仍然是一个中心问题。 在赛场上。 我们结合化学和生物学的方法来研究转录的其他难以处理的特征。 监管者。我们利用序列特定的DNA结合化合物(聚酰胺)来靶向特定的DMA 序列，并且它们可以很容易地修改以承载丰富的功能模块阵列。在建议的 工作中，我们将阐明牙外和超双胸两种高度协同结合DNA的基础 保守的发育调节器。我们将应用这种理解来开发精确定制的产品 与细胞类型的特定转录因子协同靶向基因的合成调节剂。最后，我们 将测试我们的人工转录因子调节细胞和活体中基因的能力。 我们工作的最终目标是产生能够调节靶基因表达的小分子 以一种理想的方式表达基因。作为设计转录因子，这些分子将在 解剖控制细胞命运和疾病的转录网络。也有潜在的治疗作用 用于治疗由转录调控异常引起的多种疾病的药物。

ell fate is determined by sets of genes that are expressed in a programmed manner during development and cellular differentiation. Often, in diseases as diverse as diabetes and cancer, malfunctioning transcriptional regulators produce aberrant patterns of gene expression that are at the heart of the ailment. How regulatory proteins find their binding sites and regulate their targeted genes remains a central question n the field. We combine chemical and biological approaches to study otherwise intractable features of transcriptional regulators. We utilize sequence-specific DNA binding compounds (polyamides) to target specificDMA sequences, and they can be readily modified to bear a rich array of functional modules. In the proposed work, we will elucidate the basis of cooperative DNA binding by Extradenticle and Ultrabithorax, two highly conserved developmental regulators. We will apply that understanding to develop precisely tailored synthetic regulators that target genes cooperatively with cell-type specific transcription factors. Finally, we will test the ability of our artificial transcription factors to regulate genes in cells and in living organisms. The ultimate goal of our work is to generate small molecules that can regulate the expression oftargeted genes in a desired manner. As designer transcription factors, these molecules will have tremendous value in dissecting transcriptional networks that govern cell fate and disease. The aslo have potential as therapeutic agents for a variety of diseases that are caused by aberrant transcriptional regulation.