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

职业：剖析先锋转录因子凝聚物的相行为及其在基因调控中的作用

• 批准号: 2239500
• 负责人: Priya Banerjee
• 金额: $ 92.5万
• 依托单位: SUNY at Buffalo
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2239500&HistoricalAwards=false
• 关键词: CAREER; Dissecting; Phase; Behavior; Pioneer

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.

DNA分子聚集在一起形成染色体，存储生命信息，就像电脑硬盘一样。 基因是信息的比特，通常在需要信息之前被“关闭”。一种称为转录因子（TF）的特殊蛋白质可以打开基因，最终导致蛋白质的产生和细胞功能。 解读转录因子如何调节基因表达对于理解它们在多细胞生物体发育中的功能至关重要。该项目将测试一个假设，即就像蜘蛛网上的露珠一样，TF在DNA上形成液体状液滴，每个液滴都可以提供一个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代表性不足的学生参与跨学科教育和研究的范围，激发高需求的城市高-来自布法罗公立学区的学生在STEM职业选择中通过无障碍科学和通过当地和全球艺术展览在外行观众中促进生物物理学素养。基因表达对于决定一个人的未来至关重要。细胞的命运，即使许多需要表达的基因被压缩成致密的染色质而无法表达。先锋转录因子（PTFs）可以启动染色质重塑到一个可访问的状态。我们推测，这种活动是促进形成相分离的枢纽含有转录因子，RNA聚合酶和蛋白质复合物负责核小体重塑。该项目旨在确定控制PTFs相分离的物理原理，以及PTFs与DNA和其他必要辅因子的共缩合如何调节其活性。这些研究有望为以下两个方面提供新的见解：（a）相分离在基因组组织中的作用;（B）先驱转录因子对基因的调控机制。协同教育、外展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-长期研究目标是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计划共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响审查标准。

项目成果

Dissecting the biophysics and biology of intrinsically disordered proteins.

剖析本质上无序蛋白质的生物物理学和生物学。

• DOI: 10.1016/j.tibs.2023.10.002
• 发表时间: 2024
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: Banerjee,PriyaR;Holehouse,AlexS;Kriwacki,Richard;Robustelli,Paul;Jiang,Hao;Sobolevsky,AlexanderI;Hurley,JenniferM;Mendell,JoshuaT
• 通讯作者: Mendell,JoshuaT