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

项目总结 了解基因组的功能是21世纪最大的挑战之一。编码在 它的DNA序列是几种细胞类型的蓝图。然而，它仍然是一个谜，如何充分 出现了各种各样的表型，以及它们是如何保持的。越来越清楚的是，表观基因组- DNA和组蛋白的共价修饰起着至关重要的作用。全基因组图谱分析 表观遗传修饰已经阐明了细胞类型的特异性和存在的一套不同的组合 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 因此，表观基因组的调节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，我们提出了几种新的建模方法，它们将解决我们的 理解表观基因组和基因组之间的相互关系。首先，我们将对一个粗略的- 自下而上的粒化染色质模型使用一种新的深度学习算法生成准确的和 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。从这一努力中获得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可获得性。其次，我们将调查表观遗传修饰在调节长程 通过开发能够从头开始的预测模型，实现监管要素之间的相互作用 三维基因组组织的重建。该项目将导致对全球范围内的 表观基因组在细胞分化和细胞命运决定中的作用。更好地理解 表观基因组和基因组之间的相互关系可以指导 用于修饰表观基因组以适应持久和可逆变化的工程方法的发展 作为对抗癌症等疾病的一种新策略。

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.