From epigenome to genome and back: disentangling the relationship between epigenetic modifications and chromatin organization

项目概要 了解基因组如何发挥作用是 21 世纪最大的挑战之一。编码内 它的 DNA 序列是多种细胞类型的蓝图。然而，如何充分发挥作用仍是一个谜。 各种表型的出现以及它们是如何维持的。越来越明显的是，表观基因组—— DNA 和组蛋白的共价修饰发挥着至关重要的作用。全基因组分析 表观遗传修饰阐明了细胞类型特异性和多种组合的存在 与基因表达水平密切相关的模式。从这些数据推断因果关系 然而事实证明这是具有挑战性的。了解为建立和实施提供信息的机制的工作知识 因此，表观基因组的调控及其对基因表达和细胞表型的影响仍然存在 难以捉摸。在这个项目中，我们提出了几种新颖的建模方法，这些方法将解决我们的关键差距 了解表观基因组和基因组之间的相互关系。首先，我们将参数化一个粗略的 使用新颖的深度学习算法自下而上地构建颗粒染色质模型，以生成准确且 染色质二级结构的综合表征及其对 DNA 序列的敏感性， 核小体重复长度、离子浓度、翻译后修饰和相分离液体 由本质上无序的蛋白质形成的液滴。这项工作的高分辨率染色质结构将 阐明不同的表观遗传修饰如何通过调节核小体包装影响基因表达 和DNA可及性。其次，我们将研究表观遗传修饰在介导长程 通过开发预测模型，监管要素之间的相互作用将能够从头开始 三维基因组组织的重建。该项目将使人们对以下方面的作用有一个全球认识： 细胞分化和细胞命运决定中的表观基因组。加深了对 该研究计划的表观基因组和基因组之间的相互关系可以指导 开发工程方法来修改表观基因组以实现持久和可逆的变化 作为对抗癌症等疾病的新策略。

PROJECT SUMMARY Understanding how the genome functions is one of the greatest challenges of the 21st century. Encoded within its DNA sequences are the blueprints for several cell types. Nevertheless, it remains a mystery how the full variety of phenotypes arise, and how they are maintained. It is becoming increasingly clear that the epigenome— covalent modifications to the DNA and histone proteins—plays a crucial role. Genome-wide profiling of epigenetic modifications has clarified cell type specificity and the presence of a diverse set of combinatorial patterns that are strongly correlated with gene expression levels. Inferring causal relationships from these data has proved challenging, however. A working knowledge of the mechanisms that inform the establishment and regulation of the epigenome, and its impact on gene expression and cellular phenotype, therefore, remain elusive. In this project, we propose several novel modeling approaches which will address the key gaps in our understanding of the interrelationship between the epigenome and genome. First, we will parameterize a coarse- grained chromatin model from the bottom-up using a novel deep learning algorithm to generate an accurate and comprehensive characterization of chromatin secondary structure, and its sensitivity to DNA sequence, nucleosome repeat length, ionic concentrations, post-translational modifications, and phase-separated liquid- droplets formed by intrinsically disordered proteins. High resolution chromatin structures from this effort will elucidate how different epigenetic modifications impact gene expression by regulating nucleosome packaging and DNA accessibility. Second, we will investigate the role of epigenetic modifications in mediating long-range interactions between regulatory elements by developing a predictive model which will enable de novo reconstruction of three-dimensional genome organization. This project will result in a global view of the role of the epigenome in cell differentiation and cell fate determination. An improved understanding of the interrelationship between the epigenome and the genome from this research program can guide the development of engineering approaches to modify the epigenome for both long lasting and reversible changes as a novel strategy for combating diseases such as cancer.