Development and Applications of 'Designer Chromatin'

“设计师染色质”的开发和应用

• 批准号: 8875016
• 负责人: Tom Muir
• 金额: $ 30.09万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875016
• 关键词: Area; Binding; Biochemical; Biochemical Genetics; Biochemical Reaction; Biochemistry; Biological; Biological Models; Biology; Cataloging; Catalogs; Cells; Cellular biology; Chemicals; Chromatin; Chromatin Modeling; Chromatin Structure; Complex; DNA; DNA Repair; Data; Data Set; Development; Enzymes; Eukaryotic Cell; Floods; Fluorescence Spectroscopy; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Genomic DNA; Genomics; Goals; Heterochromatin; Higher Order Chromatin Structure; Histone H2A; Histone H2B; Histones; Human Biology; Investigation; Lead; Libraries; Link; Lysine; Maintenance; Methods; Methylation; Methyltransferase; Molecular; NMR Spectroscopy; Non-Histone Chromosomal Proteins; Nuclear; Nucleosomes; Plant Roots; Post-Translational Protein Processing; Problem Solving; Process; Proteins; Proteomics; Reader; Regulation; Research; Research Proposals; Resolution; Role; Series; Signal Transduction; Site; Solutions; Structure; Surveys; Technology; Therapeutic; Thermodynamics; Ubiquitin; Work; base; chromatin remodeling; design; epigenomics; genetic approach; genome-wide; histone methyltransferase; histone modification; human disease; leukemia treatment; new technology; news; next generation sequencing; novel; programs; public health relevance; tool; uH2A; yeast genetics

DESCRIPTION (provided by applicant): A research program will be undertaken to deepen our understanding of the molecular mechanisms underlying the regulation of chromatin structure and function. Chromatin, the complex of genomic DNA with histone and non-histone proteins, is the physiologically relevant form of all eukaryotic genomes. Once thought of as merely a packaging solution for the DNA, it is now accepted that chromatin serves as a dynamic signaling platform to regulate DNA access. Indeed, this research proposal is rooted in the idea that there exist heritable functional "states" of chromatin, representing a fundamental regulatory mechanism that operates outside of the DNA itself, that help set the transcriptional potential of a gene locus. Mistakes made in establishing and maintaining these chromatin states, governed by chromatin remodeling activities, lead to the misregulation of genes with far-reaching implications for human biology and human disease. Building on some recent breakthroughs on the synthesis and application of what we call 'designer chromatin', we will integrate chemical, biochemical, biophysical and genetic tools for the purpose of obtaining a deeper understanding of the physicochemical principles underlying the regulation of chromatin function. The immediate focus will be on the role of histone ubiquitylation in chromatin biology (aims 1 and 2), however, new tools will also be developed that broaden the scope of this work significantly into other aspects of chromatin regulation and, importantly, that do so by greatly accelerating mechanistic biochemistry (aims 2 and 3). In the short term, this research is designed to reveal the molecular mechanism(s) by which histone ubiquitylation orchestrates downstream biochemistry on chromatin, an understanding that may aid the rational design of therapeutics directed at inhibiting enzymes such as the methyltransferase, hDot1L, for the treatment of leukemias. In the long term, the technologies that will be developed as part of this work, will have broad utility in the chromatin area. .

描述（由申请人提供）：将进行一项研究计划，以加深我们对调节染色质结构和功能的分子机制的理解。染色质是基因组DNA与组蛋白和非历史蛋白的复合物，是所有真核基因组的生理相关形式。一旦被认为仅仅是DNA的包装解决方案，现在就可以接受染色质作为调节DNA访问的动态信号平台。的确，该研究建议源于以下观点：存在染色质的可遗传功能“状态”，代表了在DNA本身之外运行的基本调节机制，这有助于树立转录潜力 基因基因座。在建立和维持这些染色质状态的错误中，受染色质重塑活性支配的错误导致对人类生物学和人类疾病具有深远影响的基因的不利影响。基于关于我们所谓的“设计师染色质”的合成和应用的一些突破，我们将整合化学，生化，生物物理和遗传学工具，以便更深入地了解染色质功能调节的物理化学原理。直接的重点将放在组蛋白泛素化在染色质生物学中的作用（目标1和2），但是，还将开发新的工具，从而将这项工作的范围显着扩大到染色质调节的其他方面，并且重要的是，通过极大地加速了机械生物化学（目标2和3）。在短期内，这项研究旨在揭示组蛋白泛素化的分子机制，通过该机制在染色质上精心策划下游生物化学，这种理解可能有助于抑制甲基转移酶，HDOT1L等治疗酶的治疗疗法的理性设计，以治疗白血病。从长远来看，将作为这项工作的一部分开发的技术将在 染色质区域。 。