EAGER: Cracking the histone code with engineered histone readers

在所有真核生物中，组蛋白是基因组和生物体生物学的核心。组蛋白翻译后的化学修饰是由具有组蛋白阅读器结构域的蛋白质翻译的“密码”的基础，它提供了组蛋白翻译后修饰分布中维持的信息与高阶生物过程（如基因表达，DNA修复）之间的关键联系。为了理解组蛋白编码，我们的目标是加速发现基因组和组蛋白解读域之间的特定相互作用。新技术已经彻底改变了我们在序列水平上研究基因组的能力。然而，当涉及到测量与基因组相互作用的蛋白质时，由于工具箱的限制，我们对基因组生物学的理解落后了。这项工作的目的是开发一种新的方法，如果成功的话，将作为一种广泛适用的工具，用于测量基因组中不同环境下和不同发育阶段的不同解读域的活性。我们设想这个工具的部署作为一个潜在的变革框架，研究不同生物的染色质生物学。我们的实验室也致力于促进STEM的多样性和包容性。讨论的初步工作和提议的工作将继续通过美国国家科学基金会加州少数民族参与联盟（CAMP）学者计划为本科生研究人员提供机会。我们将尝试一种新的但未经测试的方法来测量组蛋白读取器的全基因组靶向性。我们将通过研究组蛋白修饰和涉及DNA修复和生物体发育的读取器来测试这种方法。这项工作旨在促进对组蛋白修饰如何通过与组蛋白阅读器结合的蛋白质转化为高阶生物信息的统一理解。如果成功，这项工作将产生一个广泛有用的系统，以帮助破译组蛋白如何协调基因组和生物体生物学。该方法最终可能成为从农业到人类健康更可靠的表观基因组诊断工具的基础。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。

Histones are central to genome and organism biology in all eukaryotes. Histone post-translational chemical modifications underlie a “code" translated by proteins with histone reader domains, which provide the critical link between the information maintained in the distribution of histone post-translational modifications and higher-order biological processes (e.g. gene expression, DNA repair). To understand this histone code, we aim to accelerate the discovery of specific interactions between genomes and histone reader domains. New technologies have revolutionized our ability to study genomes at the sequence level. Yet, our understanding of genome biology lags behind due to a more limited toolkit when it comes to measuring the proteins that interact with genomes. This work aims to develop a new method that, if successful, would serve as a broadly applicable tool for measuring the activity of different reader domains across the genome, under different environments, and across development. We envision the deployment of this tool as a potentially transformative framework for studying chromatin biology in diverse organisms. Our lab is also committed to promoting diversity and inclusion in STEM. The preliminary work discussed and proposed work will continue to provide opportunities to undergraduate researchers through the NSF California Alliance for Minority Participation (CAMP) Scholars program. We will attempt a new but untested method to measure genome-wide targeting by histone readers. We will test the approach through the study of histone modifications and readers involved in DNA repair and organism development. This work aims to advance a unified understanding of how histone modifications are translated into higher-order biological information via proteins that bind them by histone readers. If successful, this work will yield a broadly useful system to help decipher how histones orchestrate genome and organism biology. The proposed method could eventually underlie more reliable epigenome diagnostic tools from agriculture to human health.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.