Molecular mechanisms of chromatin and epigenetic regulation

项目概要 我们研究计划的长期目标是确定调节染色质的分子机制 修改信号。我们特别感兴趣的是了解 DNA 之间的复杂关系 甲基化和组蛋白翻译后修饰；基因组可及性的两个关键表观遗传调节因子 和功能。在这个广泛的框架内，我们提出以下问题：1）染色质的书写者和擦除者是如何工作的？ 修饰调节，2）核蛋白及其复合物如何与表观遗传相互作用（即读取） 标记来执行其染色质调节功能，以及 3) 染色质信号传导的失调如何影响 导致人类疾病？我们目前的研究重点是 UHRF1，一种 E3 泛素连接酶， 负责维持 DNA 甲基化主要部分的途径的基石 哺乳动物细胞。我们最近证明 UHRF1 是 DNA 甲基化的关键调节因子 通过其相互关联的读者和作者活动对组蛋白 H3 进行遗传。虽然细节如何 UHRF1 执行其调节功能的工作已开始被揭示，我们的知识存在重大差距 DNA 甲基化调控以及 UHRF1 在此过程中的作用的基本分子了解。项目 在这个框架下的实验室中，人们会提出以下问题：1) UHRF1 如何与染色质相互作用并对其进行修饰，2) 什么是 UHRF1、DNA 甲基化和基因组可及性之间的关系，3) 组蛋白的作用是什么 DNA甲基化调节中的泛素化，以及4)结构相关蛋白UHRF2如何调节 DNA甲基化？通过多学科和协作研究计划，利用优势 染色质和表观遗传学的生物化学、生物物理、结构、基因组、蛋白质组和细胞研究 调控，我们希望将表观遗传机制的基础知识转化为治疗益处。

PROJECT SUMMARY The long-term goal of our research program is to define molecular mechanisms regulating chromatin modification signaling. We are particularly interested in understanding the complex relationship between DNA methylation and histone posttranslational modifications; two key epigenetic regulators of genome accessibility and function. Within this broad framework, we question 1) how are the writers and erasers of chromatin modifications regulated, 2) how do nuclear proteins and their complexes interface with (i.e., read) epigenetic marks to perform their chromatin regulatory functions, and 3) how does deregulation of chromatin signaling contribute to human disease? Our current studies are focused on UHRF1, an E3 ubiquitin ligase that is the cornerstone of a pathway responsible for maintaining a major portion of the DNA methylation found in mammalian cells. We recently showed that UHRF1 functions as a key regulator of DNA methylation inheritance through its interconnected reader and writer activities toward histone H3. While details of how UHRF1 performs its regulatory function are beginning to be uncovered, major gaps in knowledge exist in our basic molecular understanding of DNA methylation regulation and the role of UHRF1 in this process. Projects in the lab under this framework will question 1) how does UHRF1 interact with and modify chromatin, 2) what is the relationship between UHRF1, DNA methylation, and genome accessibility, 3) what is the role of histone ubiquitination in DNA methylation regulation, and 4) how does the structurally related protein UHRF2 regulate DNA methylation? Through a multidisciplinary and collaborative research program that leverages strengths in biochemical, biophysical, structural, genomic, proteomic, and cell-based studies of chromatin and epigenetic regulation, we hope to translate basic knowledge of epigenetic mechanism into therapeutic benefit.