Modular design of synthetic transcriptional regulators

命运是由发育过程中以编程方式表达的一组基因决定的 和细胞分化。通常，在糖尿病和癌症等多种疾病中，功能失调 转录调节因子产生异常的基因表达模式，这是疾病的核心。 调节蛋白如何找到其结合位点并调节其靶基因仍然是一个中心问题 现场。 我们结合化学和生物学方法来研究转录的其他棘手特征 监管机构。我们利用序列特异性 DNA 结合化合物（聚酰胺）来靶向特定 DMA 序列，并且它们可以很容易地进行修改以承载丰富的功能模块。在提议的 在这项工作中，我们将阐明 Extradenticle 和 Ultrabithorax 这两个高度相关的 DNA 协同结合的基础。 保守的发育调节因子。我们将运用这种理解来开发精确定制的 与细胞类型特异性转录因子合作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生物体中基因的能力。 我们工作的最终目标是产生能够调节靶标表达的小分子 基因以所需的方式。作为设计转录因子，这些分子将在以下方面具有巨大价值： 剖析控制细胞命运和疾病的转录网络。也有治疗潜力 用于治疗由异常转录调控引起的多种疾病。

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.