Mechanistic Investigation and Engineering of Histone Reader Proteins

抽象的。 组蛋白翻译后修饰（PTM），包括赖氨酸， 甲基化和酰化在染色质重塑中的作用已经很好地建立，但是组蛋白的新作用 疾病中的PTM不断被发现。这个快速发展的领域需要 开发新的分子方法来探测这些PTM的生物学影响。 在此，我们重点研究了作为阅读蛋白的赖氨酸甲基化和酰化的阅读蛋白 负责感知PTM并触发生物学结果，并且两者都具有 生物医学相关性。我们的研究将包括开发新的化学生物学工具 研究结合机制，提高PTM的检测，并生成设计师 核小体研究双重PTM在生物学途径中的作用。这项研究预计将 提高开发这两类药物的选择性抑制剂和分子探针的能力， proteins.开发新方法来创建新的传感方法和设计师 核小体，我们将利用阅读器蛋白质的固有选择性来开发工程化的 阅读器蛋白（eReaders和eWriters），用于传感、标记和引入双PTM， 一种选址的方式。这一共同努力将通过提供新的见解和 研究依赖于这些PTM的生物学途径及其在疾病中的作用的新工具。

Abstract. The integral roles of histone post-translational modifications (PTMs), including lysine methylation and acylation, in chromatin remodeling is well established, but new roles of histone PTMs in disease are continually discovered. This rapidly evolving field necessitates the development of new molecular approaches to probe the biological impacts of these PTMs. Herein we focus on the reader proteins for lysine methylation and acylation as reader proteins are responsible for sensing the PTM and triggering the biological outcome, and both r have biomedical relevance. Our research will encompass development of new chemical biology tools to investigate binding mechanisms, improve detection of PTMs, and to generate designer nucleosomes to study the role of dual PTMs in biological pathways. This research is expected to advance the ability to develop selective inhibitors and molecular probes for these two classes of proteins. To develop new methods for creating new sensing methods and designer nucleosomes, we will exploit the inherent selectivity of reader proteins to develop engineered reader proteins (eReaders and eWriters) for sensing, labeling, and introduction of dual PTMs in a site selective manner. This combined effort will advance the field by providing new insight and new tools to study the biological pathways that depend on these PTMs and their role in disease.