URoL: Epigenetics 2: Learning the rules of dynamic epigenetic regulation

URoL：表观遗传学2：学习动态表观遗传调控的规则

• 批准号: 2021552
• 负责人: Georg Seelig
• 金额: $ 252.47万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2021552&HistoricalAwards=false
• 关键词: URoL; Epigenetics; Learning; rules; dynamic

In the nucleus of a eukaryotic cell, the DNA genome can be chemically modified to confer additional, so-called epigenetic, coding information. A central unanswered question in regulatory biology is how epigenetic information is decoded and used by cells as they grow and differentiate. This project aims to address that question by first developing experimental and computational strategies to predict how the genome and its epigenetic modifications are used and then testing the validity of the predictions. The testing will be done through experiments in simple cellular systems, as well as in cells programmed to differentiate into components of the human immune system. The results are expected to reveal regulatory ‘rules’ that can be used to engineer desirable cellular outcomes. The project will have educational impact by partnering with an existing program (Rainier Scholars, www.rainiercholars.org) to broaden participation in STEM by offering a pathway to college graduation for low-income students of color. In addition, research results from this project will be incorporated in development of course modules to teach design principles of epigenetic regulation at both participating institutions, the University of Washington and California Institute of Technology. Epigenetic regulation is central to all aspects of human biology. However, despite its centrality and the wealth of molecular information already collected, we still lack a predictive understanding of epigenetic control. This project combines synthetic biology, developmental biology, and computational machine learning approaches, to develop and validate predictive models of how chromatin state, sequence context, and specific regulators together establish gene expression state. These models will provide three key benefits. First, they will provide fundamental biological insight into the architecture of eukaryotic gene regulation. Second, they will permit engineering of synthetic chromatin-based regulatory systems that provide useful functionality, including the ability to establish stable gene expression states. Such synthetic systems would enable cell-based therapies that utilize the machinery of chromatin regulation to establish, maintain, and change cellular states in response to environmental conditions, even in cells participating in immune responses and other complex processes. Third, these models will help researchers understand how eukaryotic organisms harness chromatin regulation to control cell state transitions in their development. This knowledge not only will enhance the ability to interface with the natural cell fate control circuitry, but also will reveal design principles for optimizing the function of synthetic chromatin regulatory systems.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.

在真核细胞的细胞核中，DNA基因组可以被化学修饰以赋予额外的所谓表观遗传编码信息。调控生物学中一个尚未回答的核心问题是，细胞在生长和分化时如何解码和使用表观遗传信息。该项目旨在通过首先开发实验和计算策略来预测基因组及其表观遗传修饰如何使用，然后测试预测的有效性来解决这个问题。 该测试将通过简单的细胞系统以及编程分化为人类免疫系统组成部分的细胞中的实验来完成。 这些结果有望揭示可用于设计理想细胞结果的监管“规则”。该项目将通过与现有计划（Rainier Scholars，www.rainiercholars.org）合作，通过为低收入的有色人种学生提供大学毕业的途径，扩大STEM的参与，从而产生教育影响。此外，该项目的研究成果将被纳入课程模块的开发，以在参与机构华盛顿大学和加州理工学院教授表观遗传调控的设计原则。 表观遗传调控是人类生物学各个方面的核心。然而，尽管它的中心地位和丰富的分子信息已经收集，我们仍然缺乏一个预测性的理解表观遗传控制。该项目结合了合成生物学，发育生物学和计算机器学习方法，以开发和验证染色质状态，序列背景和特定调控因子如何共同建立基因表达状态的预测模型。 这些模式将提供三个主要好处。首先，他们将提供基本的生物学洞察真核基因调控的架构。其次，它们将允许基于合成染色质的调控系统的工程化，该系统提供有用的功能，包括建立稳定的基因表达状态的能力。这样的合成系统将使得基于细胞的疗法能够利用染色质调节机制来建立、维持和改变细胞状态以响应环境条件，甚至在参与免疫应答和其他复杂过程的细胞中。第三，这些模型将帮助研究人员了解真核生物如何利用染色质调控来控制细胞在发育过程中的状态转换。这些知识不仅将增强与天然细胞命运控制电路的接口能力，还将揭示优化合成染色质调控系统功能的设计原则。该奖项反映了NSF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。

项目成果

In search of lost time: Enhancers as modulators of timing in lymphocyte development and differentiation.

• DOI: 10.1111/imr.12946
• 发表时间: 2021-03
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Chu JM;Pease NA;Kueh HY
• 通讯作者: Kueh HY

Tunable, division-independent control of gene activation timing by a polycomb switch.

• DOI: 10.1016/j.celrep.2021.108888
• 发表时间: 2021-03-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Pease NA;Nguyen PHB;Woodworth MA;Ng KKH;Irwin B;Vaughan JC;Kueh HY
• 通讯作者: Kueh HY