URoL: Epigenetics 2: Robustness and Adaptability of the Dynamic Epigenome: A Multiscale Approach

细胞在自然环境中经历了各种不可预见的挑战。在这种情况下，改变往往不是一种选择。细胞不可避免地会找到新的方法来适应和生存在暴露于急性压力下。接触抗生素的细菌细胞通过改变其DNA序列获得耐药性。植物根据它们暴露在寒冷环境中的时间来决定它们的开花时间。当癌细胞暴露于化疗药物时，会产生耐药性，对治疗构成重大挑战，并使患者预后恶化。在许多情况下，这些适应性变化是表观遗传的——它们导致基因表达的改变，而基因蓝图没有任何改变。与基因突变相比，表观遗传变化可以是短暂的、可遗传的和可逆的，为细胞创新提供了多种途径。每个细胞核内的数千个基因就像一个可调节的旋钮，可以改变细胞的适应性。我们不知道细胞是如何选择转动哪个旋钮的，做出错误的选择可能会带来灾难性的后果。这个由美国国家科学基金会资助的研究项目旨在了解形成细胞内部运作的基本规则。这个研究项目捕捉细胞内分子之间的混乱碰撞，这些碰撞可以协同工作，帮助细胞做出准确的、适应性的决定。该项目还寻求通过对跨学科研究和学习的独特强调，广泛影响密歇根州的高中和本科教育。理解引导细胞做出适应性决策的生命基本规则，需要跨学科的工具来捕捉跨越不同时间和长度尺度的细胞过程。由于表观遗传变化即使在没有细胞分裂的情况下也会发生，并且不是永久性的，因此它们会导致快速、可逆和适应性的细胞反应，对细胞的生长和存活产生深远的影响。本研究使用高分辨率成像来可视化细胞中的单分子，微流控平台来揭示单个细胞内的决策事件，以及自动连续培养方法来研究细胞群体的动态。这些多维视角的综合和整合将使数学模型的发展具有预测这些复杂调控网络的紧急特性的潜力。最终，这些研究的结果将是一套规则，这些规则将定义适应性表观遗传状态，就像基因突变一样，如何代表真核生物基因组中的可进化特征。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。

Cells experience a wide range of unforeseen challenges in their natural environment. Under these circumstances, change is often not a choice. Cells inevitably find new ways to adapt and survive upon exposure to acute stress. Bacterial cells that are exposed to antibiotics acquire resistance through changes to their DNA sequence. Plants make decisions about their flowering times based on their time of exposure to cold conditions. Cancer cells, when exposed to chemotherapeutic agents, can become resistant, posing a significant challenge to treatment and worsening patient outcomes. In many cases, these adaptive changes are epigenetic - they result in gene expression changes without any alterations to the genetic blueprint. In contrast to genetic mutations, epigenetic changes can be transient, heritable and reversible providing diverse pathways for cellular innovation. The thousands of genes within the nucleus of each cell serve as tunable knobs that can alter cell fitness. We do not understand how cells choose which knobs to turn, and making the wrong choice could prove catastrophic. This NSF-funded research program aims to understand the fundamental rules that shape the inner workings of the cell. This research program captures the chaotic collisions between molecules within a cell which can work in unison to help cells make accurate, adaptive decisions. This project also seeks to broadly impact high school and undergraduate education in Michigan through a unique emphasis on interdisciplinary research and learning. Understanding the fundamental rules of life that guide cells to make adaptive decisions requires interdisciplinary tools that capture cellular processes across different time and length scales. Because epigenetic changes can occur even without cell division and are not permanent, they lead to a rapid, reversible, and adaptive cellular response that has profound consequences for cell growth and survival. This research uses high-resolution imaging to visualize single molecules in cells, microfluidic platforms to reveal decision making events within individual cells, and automated continuous culture methods to investigate the dynamics of cell populations. The synthesis and integration of these multi-dimensional viewpoints will enable the development of mathematical models with the potential to predict emergent properties of these complex regulatory networks. Ultimately, the outcome of these studies will be a set of rules that define how adaptive epigenetic states, much like genetic mutations, represent evolvable traits in eukaryotic genomes.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.