Collaborative Research: Molecular and Structural Mechanism of histone binding by the epigenetic regulator UHRF2

合作研究：表观遗传调节因子 UHRF2 结合组蛋白的分子和结构机制

• 批准号: 1716403
• 负责人: Raymond Trievel
• 金额: $ 4.42万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1716403&HistoricalAwards=false
• 关键词: Collaborative; Research; Molecular; Structural; Mechanism

Epigenetics is a layer of information that exists on top of the regular genome to regulate the expression of genes; the molecules that orchestrate this information can contribute to human health and disease. Two epigenetic molecules, called UHRF1 and UHRF2, have distinct cellular functions, but are not well characterized at the molecular level. The proposed research seeks to determine the molecular differences by which UHRF1 and UHRF2 interact with epigenetic material. The project will establish a productive and collaborative research program that provides valuable scientific training for ~12-14 undergraduate students at Eastern Michigan University (EMU). Strong mentorship and cross-disciplinary training will provide students with critical thinking and research skills so they are prepared to succeed in future biomedical careers. The research plan will also be integrated into undergraduate biochemistry lab courses to give additional students the learning benefits of research. Together, the proposed work will strengthen the academic and research environment at EMU and increase basic knowledge in the area of epigenetics. Histone reader proteins engage epigenetic modifications and play a central role in the regulation of many nuclear processes such as transcription, DNA replication and DNA repair. The detailed molecular mechanisms by which many of these proteins mediate histone recognition remain unknown; thus this represents a major gap in our current understanding of how these proteins impart specificity and regulate the epigenetic apparatus. This research focuses on the histone reader protein UHRF2, a close homolog of UHRF1 with distinct nuclear functions. While UHRF1-histone interactions are well studied, very little is known on the molecular and structural requirements of histone recognition by UHRF2. The goal of this project is to determine the molecular and structural mechanisms by which the histone binding domains of UHRF2 functionally interact with histone H3. Equilibrium binding assays, mutagenesis and crystallographic approaches will be utilized to elucidate the mechanisms that dictate histone-binding specificity between UHRF1 and UHRF2. This research will provide molecular insights as to how histone reader proteins distinguish and engage their cognate PTMs and advance fundamental understanding of epigenetic regulation.

表观遗传学是存在于常规基因组之上的一层信息，用于调节基因的表达；协调这些信息的分子可以促进人类健康和疾病。两种表观遗传分子，称为 UHRF1 和 UHRF2，具有不同的细胞功能，但在分子水平上尚未得到很好的表征。拟议的研究旨在确定 UHRF1 和 UHRF2 与表观遗传物质相互作用的分子差异。该项目将建立一个富有成效的合作研究项目，为东密歇根大学 (EMU) 约 12-14 名本科生提供宝贵的科学培训。强有力的指导和跨学科培训将为学生提供批判性思维和研究技能，以便他们为未来的生物医学职业生涯取得成功做好准备。该研究计划还将纳入本科生生物化学实验室课程，让更多学生从研究中受益。总之，拟议的工作将加强 EMU 的学术和研究环境，并增加表观遗传学领域的基础知识。组蛋白阅读器蛋白参与表观遗传修饰，并在转录、DNA 复制和 DNA 修复等许多核过程的调节中发挥核心作用。许多这些蛋白质介导组蛋白识别的详细分子机制仍然未知。因此，这代表了我们目前对这些蛋白质如何赋予特异性和调节表观遗传机制的理解中的一个重大差距。这项研究的重点是组蛋白阅读器蛋白 UHRF2，它是 UHRF1 的密切同源物，具有不同的核功能。虽然 UHRF1-组蛋白相互作用已得到充分研究，但对于 UHRF2 识别组蛋白的分子和结构要求却知之甚少。该项目的目标是确定 UHRF2 的组蛋白结合域与组蛋白 H3 功能性相互作用的分子和结构机制。将利用平衡结合测定、诱变和晶体学方法来阐明决定 UHRF1 和 UHRF2 之间组蛋白结合特异性的机制。这项研究将为组蛋白阅读器蛋白如何区分和参与其同源 PTM 提供分子见解，并促进对表观遗传调控的基本理解。