CAREER: Computational and statistical methods for allele-specific chromatin structure analysis

三维基因组组织在基因调控中起着重要作用。这种组织的一个层次由包裹在组蛋白蛋白周围的DNA组成，称为染色质。高通量染色质构象捕获方法(一个例子被称为Hi-C分析)已经被开发出来，并且产生了关于3D基因组组织的大量信息。然而，大多数目前的分析工具无法区分来自二倍体生物体(如人类和其他哺乳动物)的配对(同源)母本和父本染色体的Hi-C或同等信息。这意味着无法判断母系和父系的基因拷贝(等位基因)是否会产生不同的影响。该项目将解决这一问题，并允许发展精细的、等位基因特异的染色质结构，从而阐明染色质相互作用在等位基因调控中的作用(S)以及基因组组织的更大原则。这项研究将产生新的计算和统计方法，将等位基因特定染色质结构的分析与基因表达调控结合起来；产品将包括用于3D基因组建模、比较、可视化和探索的开源软件工具。这些软件工具将向世界各地的科学家公开开放。综合研究和教育活动包括为数据科学、统计和计算基因组学等学科的本科生和研究生课程开发课程。活动将允许本科生参与研究项目，并培训研究生研究人员获得跨学科专业知识。该项目将特别面向中学生，目标是让年轻女性和未被充分代表的少数群体参与STEM学科。该项目的目标是(I)建立一个新的计算和统计框架，以等位基因特有的方式模拟3D染色质结构；(Ii)识别同源染色体对之间的结构差异；(Iii)研究染色质组织对等位基因调控的影响；以及(Iv)了解基因组结构和基因功能之间的相互作用。该项目将把精细的等位基因特异染色质结构与目前压倒性的一维功能基因组数据相结合，以发现新的等位基因特异调控元件和特征。该项目将以前所未有的分辨率阐明基因调控原理，并加强我们对基因组结构和基因表达之间相互作用的理解。这些发现将对分子细胞生物学、个人基因组学和医学具有基础性意义。关于该项目的更新和更多信息将在http://faculty.ucr.edu/~wenxiu/nsf-1751317.html.This上提供，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智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Three-dimensional (3D) genome organization plays an important role in gene regulation. One level of this organization consists of DNA wrapped around histone proteins, and is called the chromatin. High-throughput chromatin conformation capture methods (one example is called the Hi-C assay) have been developed, and yield an immense amount of information about 3D genome organization. However, most current analysis tools cannot distinguish the Hi-C, or equivalent, information that comes from the paired (homologous) maternal and paternal chromosomes in diploid organisms (like humans and other mammals). This means it is not possible to tell if there are different effects arising from the maternal and paternal copies of genes (the alleles). This project will address this problem and allow the development of fine-scale, allele-specific chromatin structures and therefore shed light on the role(s) of chromatin interactions in allelic gene regulation as well as larger principles of genome organization. This research will result in novel computational and statistical methods that combine the analysis of allele-specific chromatin structure with gene expression regulation; the products will include open-source software tools for 3D genome modeling, comparison, visualization, and exploration. These software tools will be made publicly accessible to scientists worldwide. The integrated research and educational activities include curriculum development for both undergraduate and graduate courses in subjects including data science, and statistical and computational genomics. Activities will allow undergraduate students to participate in the research project, as well as training graduate student researchers to acquire interdisciplinary expertise. The project will reach out particularly to middle school students with the goal of engaging young women and underrepresented minority groups in STEM disciplines.The goal of this project is to (i) establish a new computational and statistical framework for modeling the 3D chromatin structures in an allele-specific manner; (ii) identify structural differences between homologous chromosome pairs; (iii) investigate the impact of chromatin organization on allelic gene regulation; and (iv) understand the interplay between genome architecture and gene function. The project will integrate fine-scale allele-specific chromatin structures with the currently overwhelming amount of one-dimensional functional genomics data to discover new allele-specific regulatory elements and features. The project will elucidate gene regulation principles at an unprecedented resolution, and enhance our understanding of the interplay between genome architecture and gene expression. These findings will have fundamental significance in molecular cell biology, personal genomics, and medicine. Updates and additional information about this project will be made available at http://faculty.ucr.edu/~wenxiu/nsf-1751317.html.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.