"Developing A Comprehensive Toolkit for Chemical Inducible Epigenome Remodeling"

“开发化学诱导表观基因组重塑的综合工具包”

• 批准号: 10634575
• 负责人: Fu-Sen Liang
• 金额: $ 32.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634575
• 关键词: Adaptor Signaling Protein; Address; Biological Process; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complex; DNA Methylation; Development; Disease; Engineering; Epigenetic Process; Foundations; Future; Gene Expression; Gene Expression Regulation; Genes; Genome; Goals; Guide RNA; Heterodimerization; Histones; Individual; Location; Methods; Mutation; Nucleosomes; Pathogenesis; Pathway interactions; Play; Proteins; Research; Research Personnel; Role; Shapes; Specificity; System; Technology; Time; Variant; Work; Writing; base editing; chromatin remodeling; effectiveness testing; epigenetic regulation; epigenome; epigenome editing; genomic locus; histone modification; human disease; innovative technologies; novel therapeutic intervention; recruit; spatiotemporal; tool

Project Summary/ Abstract Distinct epigenetic mechanisms, including histone modifications, DNA methylation, chromatin remodeling and histone variant exchange, collaboratively and dynamically shape local epigenetic landscape and control gene activities. Alteration of epigenetic pathways and mutations in epigenetic regulators contribute to the pathogenesis of various human diseases. Several studies suggest that these epigenetic pathways are orchestrated to regulate activity-gene expression. Current tools to simultaneously manipulate multiple epigenetic pathways in temporal and locus specific are lacking. Such tools are necessary to precisely dissect the functional interplays and crosstalk between these distinct epigenetic mechanisms for gene regulation. To address this limitation, we propose to establish unique chemical inducible methods that integrate dCas9/gRNA-guided targeting with the orthogonal chemically induced proximity (CIP) technology to simultaneously control different epigenetic regulations including all major epigenetic pathways. We will focus on the following three aims: (i) Develop inducible dual editing platforms for diverse histone modifications; (ii) Develop chemical inducible platforms for chromatin remodeling and nucleosome editing; (iii) Develop chemical inducible editing platforms for DNA methylation and validate the orthogonal manipulation of multiple mechanisms across distinct epigenetic pathways. After finishing this work, we expect to establish a unique toolset that can be readily used by researchers in the field. This platform can be easily adapted and expanded to manipulate new epigenetic factors not tested in this study. This new epigenome editing/remodeling platform will facilitate the advancement of epigenetic research and potentially offer new directions in developing new epigenetic-based therapies.

项目总结/摘要 不同的表观遗传机制，包括组蛋白修饰，DNA甲基化，染色质重塑 和组蛋白变异交换，协同和动态地塑造局部表观遗传景观和控制 基因活动表观遗传途径的改变和表观遗传调节因子的突变有助于 各种人类疾病的发病机制。一些研究表明，这些表观遗传途径是 协调来调节活性基因的表达。目前的工具，同时操纵多个表观遗传 缺乏时间和位点特异性通路。这些工具对于精确剖析功能性 这些不同的表观遗传机制之间的相互作用和串扰的基因调控。为了解决这个 限制，我们提出建立独特的化学诱导方法，整合dCas 9/gRNA引导的 利用正交化学诱导邻近（CIP）技术靶向， 表观遗传调节包括所有主要的表观遗传途径。我们会集中达致以下三个目标：（i） 开发用于多种组蛋白修饰的诱导型双编辑平台;（ii）开发化学诱导型双编辑平台。 （iii）开发化学诱导编辑平台 DNA甲基化，并验证不同表观遗传学中多种机制的正交操作 途径。完成这项工作后，我们希望建立一个独特的工具集， 这一领域的研究人员。这个平台可以很容易地适应和扩展，以操纵新的表观遗传因子 在这项研究中没有测试。这个新的表观基因组编辑/重塑平台将促进 表观遗传学研究并可能为开发新的基于表观遗传学的疗法提供新的方向。