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测定）已经开发出来，并产生了大量关于三维基因组组织的信息。然而，目前大多数分析工具无法区分来自二倍体生物（如人类和其他哺乳动物）中配对（同源）母本和父本染色体的Hi-C或等效信息。这意味着不可能分辨出母系和父系基因拷贝（等位基因）是否产生了不同的影响。该项目将解决这一问题，并允许发展精细尺度，等位基因特异性染色质结构，从而阐明染色质相互作用在等位基因调控中的作用，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，将等位基因特异性染色质结构分析与基因表达调控相结合；这些产品将包括用于3D基因组建模、比较、可视化和探索的开源软件工具。这些软件工具将向全世界的科学家公开开放。综合研究和教育活动包括数据科学、统计和计算基因组学等学科的本科和研究生课程的课程开发。活动将允许本科生参与研究项目，并训练研究生研究人员获得跨学科的专业知识。该项目将特别针对中学生，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，以等位基因特异性的方式对三维染色质结构进行建模；（ii）鉴定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；（iv）了解基因组结构和基因功能之间的相互作用。该项目将整合精细尺度的等位基因特异性染色质结构和目前大量的一维功能基因组学数据，以发现新的等位基因特异性调控元件和特征。该项目将以前所未有的分辨率阐明基因调控原理，并增强我们对基因组结构与基因表达之间相互作用的理解。这些发现将在分子细胞生物学、个人基因组学和医学领域具有重要意义。有关该项目的更新和其他信息将在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。

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.