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，存储生命的信息，就像电脑硬盘一样。基因是信息的片段，通常被关闭，直到需要信息为止。一种名为转录因子(Tf)的特殊蛋白质启动基因，最终导致蛋白质生产和细胞功能。破译转录因子是如何调控基因表达的，对于理解它们在多细胞生物体发育中的作用是至关重要的。这个项目将检验这样一个假设，即就像蜘蛛网上的露珠一样，TF在DNA上形成液状液滴，其中每个液滴可能提供调节基因表达的特殊环境。该项目将提供基因调控领域的关键新知识。该项目的教育计划旨在通过扩大未被充分代表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，通过可接触的科学激励来自布法罗公立学区的高需求城市高中生从事STEM职业选择，并通过当地和全球艺术展在非专业观众中促进生物物理学素养。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通过压缩成密集的染色质而无法获得。先锋转录因子(PTF)可以启动染色质重塑进入可及状态。我们假设，这种活性是由含有转录因子、RNA聚合酶和蛋白质复合体的相分离中心的形成促进的，这些复合体负责核小体重塑。该项目旨在确定支配PTF相分离的物理原理，以及PTF与DNA和其他必要辅助因子的共缩合如何调节其活性。这些拟议的研究有望为(A)相分离在基因组组织中的作用以及(B)先锋转录因子对基因调控的机制提供新的见解。协同教育、外展和培训活动是对研究的补充，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来揭示基因组组织的分子机制。该项目由生物科学局分子和细胞生物科学部的分子生物物理和遗传机制计划联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.