CAREER: Dissecting Phase Behavior of Pioneer Transcription Factor Condensates and Their Role in Gene Regulation

DNA分子聚集在一起形成染色体，像电脑硬盘一样储存生命信息。基因是信息的片段，通常在需要信息时才会被关闭。一种叫做转录因子（TF）的特殊蛋白质会开启基因，最终导致蛋白质的产生和细胞功能。破译tf如何调节基因表达对于理解它们在多细胞生物发育中的功能至关重要。这个项目将测试这样一个假设：就像蜘蛛网上的露珠一样，tf在DNA上形成液体状的液滴，每个液滴可能提供一个特殊的环境来调节基因表达。该项目将为基因调控领域提供关键的新知识。该项目的教育计划旨在通过扩大代表性不足的学生参与跨学科教育和研究的范围来培养下一代生物物理学家，通过可访问的科学来激励布法罗公立学区的高需求城市高中生选择STEM职业，并通过当地和全球艺术展览提高非专业观众的生物物理学素养。基因表达对于决定细胞的命运至关重要，尽管许多需要表达的基因由于被致密的染色质压实而无法表达。先锋转录因子（PTFs）可以启动染色质重塑进入可接近状态。我们假设这种活性是由相分离中心的形成促进的，该中心含有tf、RNA聚合酶和负责核小体重塑的蛋白质复合物。该项目旨在确定控制ptf相分离的物理原理，以及ptf与DNA和其他必要的辅因子的共缩聚如何调节其活性。这些研究有望在以下方面提供新的见解：(a)相分离在基因组组织中的作用，以及(b)先锋转录因子的基因调控机制。协同的教育、推广和培训活动补充了研究，包括与本科生、高中生和普通公众的接触。完成项目目标将直接有助于PI的长期研究目标，即通过生物分子相变揭示基因组组织的分子机制。该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学和遗传机制项目共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

DNA molecules which pack together to form chromosomes, store the information for life, like a computer hard drive. Genes are the bits of information, which are generally turned ‘off’ until the information is needed. A special protein called a transcription factor (TF) turns a gene ‘on,’ ultimately leading to protein production and cellular function. Deciphering how TFs regulate gene expression is of fundamental importance to understanding their function in the development of a multicellular organism. This project will test the hypothesis that, much like dew drops on a spider web, the TFs form liquid-like droplets on the DNA where each droplet may provide a special environment that regulates gene expression. This project will provide key new knowledge in the field of gene regulation. The education plan of the project aims to train the next generation of biophysicists by broadening the scope of underrepresented student participation in cross-disciplinary education and research, inspiring high-need urban high-school students from the Buffalo Public School District in STEM career options through accessible science and promoting biophysics literacy among lay audiences through local and global art exhibitions.Gene expression is crucial for determining a cell’s fate even though many genes that need to be expressed are rendered inaccessible by compaction into dense chromatin. Pioneer Transcription Factors (PTFs) can initiate chromatin remodeling into an accessible state. We hypothesize that this activity is facilitated by the formation of phase-separated hubs containing TFs, RNA polymerases, and protein complexes responsible for nucleosome remodeling. This project aims to determine the physical principles that govern the phase separation of PTFs and how the co-condensation of PTFs with DNA and other requisite cofactors regulates their activity. The proposed studies are expected to provide new insights into (a) the role of phase separation in genome organization, and (b) the mechanism of gene regulation by pioneer transcription factors. Synergistic educational, outreach and training activities complement the research and include engagement with undergraduate students, high school students and the lay public. Completing the project goals will directly contribute to the PI’s long-term research objective to uncover molecular mechanisms of genome organization via biomolecular phase transitions.This project is jointly funded by the Molecular Biophysics and Genetic Mechanisms programs of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.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.