Investigating the role of prion-mediated epigenetic regulation in yeast using an integrative approach of multi-omics

使用多组学综合方法研究酵母中朊病毒介导的表观遗传调控的作用

• 批准号: 2332782
• 负责人: Liming Li
• 金额: $ 95.59万
• 依托单位: Northwestern University at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2332782&HistoricalAwards=false
• 关键词: Investigating; role; prion; mediated; epigenetic

Yeast prions are unusual genetic elements in the budding yeast, S. cerevisiae, transmitted as inheritable protein conformations. Due to its simplicity and amenability, yeast has become a powerful model system for studying prion biology. Multiple prion elements can co-exist in a single yeast cell, making it crucial to understand how they interact and how their interactions affect yeast cell biology. This project aims to examine how the Swi1 prion interacts with another yeast prion, Mot3, and how such prion-prion interactions affect yeast global transcription and protein-homeostasis. The proposed research program will serve as a platform to train graduate students and summer undergraduate interns. An outreach program will be established to connect Chicago-area underrepresented high school students at the Illinois Math and Science Academy with the Li research laboratory at the Feinberg School of Medicine, Northwestern University. This includes a one-day per week lab activity during the academic year and an eight-week long summer program. The ultimate broader impact is to propel disadvantaged youth in the Chicago area towards further science education and potentially to a science-oriented career.The protein determinant of the [SWI+] prion is Swi1, a subunit of the SWI/SNF chromatin remodeling complex, and the protein determinant of the [MOT3+] prion is Mot3, a transcription repressor. Both Swi1 and Mot3 are transcriptional modulators affecting yeast multicellularity. A single yeast cell can harbor both [SWI+] and [MOT3+], providing an excellent platform to study prion-prion interactions. The specific objectives of this project include: 1) Identify prion-specific changes in transcriptome and cell-to-cell heterogeneity using the technology of high-throughput single-cell RNA-sequencing. 2) Examine the genomic occupancies of important transcriptional modulators and epigenetic marks that are functionally linked to [SWI+] and/or [MOT3+] through the CUT&RUN-sequencing methodology. 3) Investigate prion-specific changes in proteomics and post-translational modifications using multiplex-labeling proteomics. The results from the proposed study will provide valuable insights into the interaction between the [SWI+] and [MOT3+] prions and their impact on global transcription and proteostasis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

酵母pr是在发芽的酵母菌葡萄球菌中的异常遗传元素，作为遗传性蛋白质构象传播。由于它的简单性和舒适性，酵母已成为研究prion生物学的强大模型系统。多个prion元素可以在单个酵母细胞中共存，这对于了解它们如何相互作用以及它们的相互作用如何影响酵母细胞生物学至关重要。该项目的目的是研究SWI1 prion如何与另一个酵母菌prion，MOT3相互作用，以及这种prion-prion相互作用如何影响酵母菌全球转录和蛋白质 - 肉眼。拟议的研究计划将作为培训研究生和夏季本科实习生的平台。将建立一项外展计划，以将伊利诺伊州数学和科学学院的芝加哥地区人数不足的高中学生与西北大学Feinberg医学院的LI研究实验室联系起来。这包括学年每周一日实验室活动和八周的夏季计划。最终的更广泛的影响是将芝加哥地区的劣势青年推向进一步的科学教育，并有可能致力于以科学为导向的职业。 SWI1和MOT3都是影响酵母多细胞性的转录调节剂。单个酵母细胞可以携带[SWI+]和[MOT3+]，为研究Prion-Prion相互作用提供了出色的平台。 该项目的特定目标包括：1）使用高通量单细胞RNA-Sequent的技术来确定转录组和细胞对细胞异质性的特定于Prion特定的变化。 2）通过剪切和运行的方法，检查了重要的转录调节剂和表观遗传标记的基因组占用率和表观遗传标记。 3）研究使用多重标记蛋白质组学的蛋白质组学和翻译后修饰的特异性变化。拟议研究的结果将为[SWI+]和[MOT3+] prions之间的相互作用及其对全球转录和蛋白质的影响提供宝贵的见解。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来获得支持的。