EAGER: Cracking the histone code with engineered histone readers

组蛋白是所有真核生物基因组和生物体生物学的核心。组蛋白翻译后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，其提供了组蛋白翻译后修饰分布中维持的信息与更高级生物过程（例如基因表达、DNA修复）之间的关键联系。为了理解这个组蛋白密码，我们的目标是加速发现基因组和组蛋白阅读器结构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，我们对基因组生物学的理解落后于测量与基因组相互作用的蛋白质的工具包。这项工作的目的是开发一种新的方法，如果成功的话，将作为一个广泛适用的工具，用于测量不同的阅读器域的活动，在不同的环境下，在整个基因组中，和整个发展。我们设想部署这个工具作为一个潜在的变革性的框架，在不同的生物体中研究染色质生物学。我们的实验室还致力于促进STEM的多样性和包容性。 初步工作讨论和拟议的工作将继续提供机会，本科研究人员通过NSF加州联盟少数民族参与（CAMP）学者计划。 我们将尝试一种新的但未经测试的方法来测量组蛋白阅读器的全基因组靶向。我们将通过组蛋白修饰的研究和参与DNA修复和生物体发育的读者来测试这种方法。 这项工作的目的是推进一个统一的理解，如何组蛋白修饰被翻译成更高层次的生物信息通过蛋白质结合他们的组蛋白读者。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编排基因组和生物体生物学。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。

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.