Mechanisms of chromatin and transcriptional regulation

染色质和转录调控机制

• 批准号: 9912773
• 负责人: Brian D Strahl
• 金额: $ 56.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912773
• 关键词: Award; Biochemical; Biology; Cell Cycle; Chromatin; DNA Maintenance; DNA Methylation; DNA Packaging; DNA Repair; DNA biosynthesis; Defect; Enzymes; Gene Expression Regulation; Genetic Transcription; Genome; Goals; Histones; Human Biology; Knowledge; Lysine; Malignant Neoplasms; Molecular; Molecular Chaperones; Mutation; Nucleosome Binding Domain; Play; Post-Translational Protein Processing; Proteins; Reader; Regulation; Role; Seminal; Therapeutic Intervention; Transcriptional Regulation; Writing; chromatin remodeling; combinatorial; human disease; new therapeutic target

Histone post-translational modifications (PTMs), chromatin-remodeling enzymes, DNA methylation, and histone chaperones play critical roles in the organization and control of our genomes. Importantly, disruption or mutation of the proteins or enzymes responsible for chromatin regulation underlies a number of human diseases, most notably cancer. Our long-term goal is to elucidate the molecular underpinnings of chromatin regulation and define how this regulation contributes to human biology and disease. Our lab has spearheaded the pursuit of this goal, making seminal discoveries that explain how the chromatin-modifying machinery “writes” and “reads” histone PTMs and how histone PTMs function in transcription, DNA replication, DNA repair, and maintenance of DNA methylation. Yet, despite considerable progress, there remain many crucial knowledge gaps. For example, it is largely unknown the extent to which histone PTMs function in a combinatorial manner. Similarly, we do not fully understand the biochemical basis for recognition of histone PTMs by the many different reader domains in chromatin- associated proteins nor do we fully understand how paired reader domains bind nucleosomes in a multivalent manner. Finally, we do not know the functions of newly identified histone PTMs, e.g., lysine crotonylation. With this MIRA award, our lab will close these knowledge gaps by answering three of the foremost fundamental questions in chromatin biology: 1) How do histone-modifying enzymes and chaperones regulate transcription, the cell cycle, and maintain chromatin integrity? 2) How do recently discovered histone PTMs such as crotonylation contribute to gene regulation? 3) To what extent do histone PTMs collaborate to regulate downstream functions in chromatin? !

组蛋白翻译后修饰 (PTM)、染色质重塑酶、DNA 甲基化和组蛋白伴侣在组织和控制中发挥着关键作用 我们的基因组。重要的是，负责的蛋白质或酶的破坏或突变 因为染色质调控是许多人类疾病的基础，尤其是癌症。 我们的长期目标是阐明染色质调控的分子基础 并定义该法规如何对人类生物学和疾病做出贡献。我们实验室有 带头追求这一目标，做出了开创性的发现，解释了如何 染色质修饰机制“写入”和“读取”组蛋白 PTM 以及组蛋白如何 PTM 在转录、DNA 复制、DNA 修复和 DNA 维护中发挥作用 甲基化。然而，尽管取得了相当大的进步，但仍然存在许多关键知识 差距。例如，组蛋白翻译后修饰 (PTM) 在多大程度上发挥作用尚不清楚。 组合方式。同样，我们也不完全了解其生化基础。 染色质中许多不同的阅读器域对组蛋白 PTM 的识别 相关蛋白质我们也不完全了解配对的阅读器结构域如何结合 以多价方式形成核小体。最后，我们不知道new的功能 鉴定了组蛋白 PTM，例如赖氨酸巴豆酰化。凭借这个 MIRA 奖项，我们的实验室将 通过回答三个最重要的基本问题来缩小这些知识差距 染色质生物学：1）组蛋白修饰酶和分子伴侣如何调节 转录、细胞周期和维持染色质完整性？ 2）最近怎么样 发现组蛋白翻译后修饰（例如巴豆酰化）有助于基因调控？ 3) 至 组蛋白 PTM 在多大程度上协作调节下游功能 染色质？ ！