CAREER: Developmental Network Architecture Underlies Patterning Precision and Robustness

所有的动物都是从一个受精卵细胞开始的。在发育过程中，这种细胞分裂，它的后代开启不同的基因亚群，形成不同类型的细胞，比如肌肉、神经和血液中的细胞。这个过程是精确的；组织和器官的大小和形状都是正确的，它们出现在正确的位置。这个过程也是稳健的；在广泛的环境和基因攻击下，发展准确地展开。然而，动物在疾病或进化中的生理变化往往是由于发育的改变。这个奖项解决了这个关键的悖论：发展如何既能缓冲变化，又能响应和适应变化，产生新的生物？就更广泛的影响而言，进入生命科学博士学位的候选人中，只有不到10%的人能获得终身教职。因此，科学培训必须包括对学术界、政府和私营部门有用的技能。该奖项将支持教会科学家如何有效沟通的努力，这是一项基本的、普遍受到重视的技能。首席研究员将扩大她所指导的创新研究生课程的范围，为本科生量身定制课程，并在网上提供模块化材料，以便其他人可以使用它。这种教学努力将造就新一代的科学家，他们善于跨学科交流，善于与公众沟通，并且具备在学术界以外的职业中非常受重视的技能。其核心假设是，发育的精确性和健壮性编码在基因调控网络的回路中，并延伸到将它们连接在一起的调控DNA中。通过研究这种电路是如何构建的，以及它们在扰动下的行为，我们可以了解它们是如何精确、健壮且可进化的。阴影增强子是驱动相同靶基因表达模式的不同调控DNA片段，可提高发育系统的精确性和稳健性，但其机制尚不清楚。DePace实验室在果蝇胚胎中进行基因调控网络的研究，因为果蝇和包括人类在内的其他动物的发育规则极其相似，但果蝇胚胎为破译潜在原理提供了实质性的实验优势。DePace实验室最近在果蝇胚胎中发现了一对阴影增强因子，它们以相反的方式对同一调节因子做出反应。本项目将使用定量实验和计算模型来探究这种新型电路的功能。目的1将确定如何控制双功能调节剂（转录因子）的活性。目的2将确定电路如何影响胚胎的模式精度和稳健性。本研究将：1)探索转录因子双功能的分子机制，这是基因组解释中的一个普遍问题；2)确定一种新的转录回路在胚胎模式精度和稳健性中的作用；3)建立一个强大的模型来研究分布式调控DNA的机制和后果，这是一个重要但研究不足的类别。

All animals begin as a single fertilized cell. During development, this cell divides and its progeny turn on distinct subsets of genes to build different types of cells like those in muscles, nerves and blood. This process is precise; tissues and organs are the correct size and shape and they occur in the correct position. This process is also robust; development unfolds accurately under a wide range of environmental and genetic assaults. Yet changes to animal physiology in disease or evolution are often due to alterations to development. This award addresses this critical paradox: how does development both buffer against change, and yet respond and adapt to change to produce new creatures? With respect to broader impacts, fewer than 10% of entering life science Ph.D. candidates will attain tenure-track academic jobs. Scientific training must therefore include skills that are useful in academia, government and the private sector. This award will support efforts to teach scientists how to communicate effectively, which is a fundamental and universally valued skill. The principal investigator will expand the scope of an innovative graduate course she directs, tailor it for undergraduates, and make modular materials available online so that other people can deploy it. This teaching effort will lead to a new generation of scientists adept at communicating across disciplines and with the public, and with skills that are highly valued in careers outside of academia. The central hypothesis is that developmental precision and robustness are encoded in the circuits of gene regulatory networks, and by extension, the regulatory DNA that wires them together. By studying how such circuits are built, and how they behave under perturbation, we can learn how they can be precise, robust and yet evolvable. Shadow enhancers, distinct pieces of regulatory DNA that drive the same target gene expression pattern, increase the precision and robustness of developmental systems but the mechanism is unknown. The DePace lab conducts their studies of gene regulatory networks in fruitfly embryos because the rules governing development are extremely similar between fruitflies and other animals, including humans, but fruitfly embryos offer substantial experimental advantages for deciphering the underlying principles. The DePace lab recently uncovered a pair of shadow enhancers in fruitfly embryos that respond to the same regulator in opposite ways. This project will interrogate the function of this novel circuit using quantitative experiments and computational models. Aim 1 will determine how the activity of the bifunctional regulator (a transcription factor) is controlled. Aim 2 will determine how the circuit affects patterning precision and robustness in the embryo. This research will: 1) probe the molecular mechanism of transcription factor bifunctionality, a general problem in interpreting the genome, 2) determine the role of a novel transcriptional circuit in embryonic patterning precision and robustness and 3) establish a powerful model for studying the mechanism and consequences of distributed regulatory DNA, which is a significant but under-studied class.