Predictable control of gene regulation through epigenetic engineering

项目摘要/摘要 最近具有里程碑意义的发现表明，除了DNA损伤外，表观遗传机制也发挥着 在癌症中起主要作用。表观遗传学在一定程度上是通过蛋白质和DNA的相互作用来调节的，这些相互作用赋予了可遗传的 基因表达状态。给癌症表观基因组下药是一项新兴的医疗技术，目前使用的 小分子抑制剂和小RNA，以破坏过度活跃的表观遗传酶。拟议的工作将 测试一种新的方式，即与染色质纤维相互作用的融合蛋白将激活的假设 带有癌症相关生化标记特定模式的治疗性基因。具体目标 是(2)使用生物信息学分析来发现支持基因可诱导变化的染色体特征 表达状态和(2)使用蛋白质工程来确定核蛋白参与的决定因素。

PROJECT SUMMARY/ ABSTRACT Recent landmark discoveries have revealed that in addition to DNA lesions, epigenetic mechanisms also play a major role in cancer. Epigenetics is mediated in part by interactions of proteins and DNA that confer heritable gene expression states. Drugging the cancer epigenome is a burgeoning medical technology that currently uses small molecule inhibitors and small RNAs to disrupt hyperactive epigenetic enzymes. The proposed work will test the hypothesis that a new modality, fusion proteins that interact with the chromatin fiber, will activate therapeutic genes at sites that bear a specific pattern of cancer-related biochemical marks. The specific aims are to (2) use bioinformatic analyses to discover chromosome features that support inducible changes in gene expression states and (2) to use protein engineering to identify determinants of nuclear protein engagement.