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

职业：等位基因特异性染色质结构分析的计算和统计方法

• 批准号: 1751317
• 负责人: Wenxiu Ma
• 金额: $ 68.82万
• 依托单位: University of California-Riverside
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1751317&HistoricalAwards=false
• 关键词: CAREER; Computational; statistical; methods; allele

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.

三维基因组结构在基因调控中起着重要作用。这种组织的一个层次由DNA包裹在组蛋白周围组成，称为染色质。已经开发了高通量染色质构象捕获方法（一个例子被称为Hi-C测定），并且产生了关于3D基因组组织的大量信息。然而，大多数当前的分析工具不能区分来自二倍体生物体（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或等同信息。这意味着不可能知道是否有不同的影响所产生的母亲和父亲的基因副本（等位基因）。该项目将解决这个问题，并允许开发精细尺度的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。这项研究将导致新的计算和统计方法，结合联合收割机的等位基因特异性染色质结构与基因表达调控的分析，产品将包括开源软件工具的三维基因组建模，比较，可视化和探索。这些软件工具将向全世界的科学家公开提供。综合研究和教育活动包括本科和研究生课程的课程开发，包括数据科学，统计和计算基因组学。活动将允许本科生参与研究项目，以及培训研究生研究人员获得跨学科的专业知识。该项目的目标是（i）建立一个新的计算和统计框架，以等位基因特异性方式建模3D染色质结构;（ii）确定同源染色体对之间的结构差异;（iii）确定染色体组之间的结构差异。（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。该项目将把精细尺度的等位基因特异性染色质结构与目前大量的一维功能基因组学数据相结合，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和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方面具有重要意义。有关该项目的更新和其他信息将在www.example.com上提供http://faculty.ucr.edu/~wenxiu/nsf-1751317.html.This奖项反映了NSF的法定使命，并被认为值得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来支持。