Mapping the 3D Genome Landscape

绘制 3D 基因组景观图

• 批准号: 9983849
• 负责人: Frank Alber
• 金额: $ 41.71万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983849
• 关键词: 3-Dimensional; Adopted; Architecture; Atlases; Automobile Driving; Biological; Biology; California; Cell Nucleus; Cell physiology; Cells; Chemicals; Chromatin; Chromosomes; Code; Collaborations; Communities; Complex; Computing Methodologies; DNA; DNA biosynthesis; Data; Defect; Disease; Enhancers; Ensure; Freezing; Gene Cluster; Gene Expression; Genetic Transcription; Genome; Genomic DNA; Institutes; Language; Link; Maps; Mass Spectrum Analysis; Methods; Modeling; Molecular Conformation; Noise; Nuclear; Nucleic Acids; Pathologic Processes; Physiological Processes; Play; Positioning Attribute; Process; Proteins; Protocols documentation; Reading; Reagent; Recording of previous events; Research; Research Personnel; Resources; Series; Software Tools; Solid; Structure; Structure-Activity Relationship; Surface; T cell differentiation; T-Lymphocyte; Techniques; Technology; Three-dimensional analysis; Time; Universities; Validation; Variant; biomacromolecule; computerized tools; data acquisition; design; genome analysis; genome-wide; improved; innovation; insight; member; new technology; novel; novel strategies; organizational structure; population based; promoter; protein complex; public health relevance; technology development; technology/technique; temporal measurement; three dimensional structure; three-dimensional modeling; tool

 DESCRIPTION: The 3D structural organization of the genome plays a key role in nuclear functions such as gene expression and DNA replication. One of the next grand challenges of biology is to determine the detailed 3D genome architecture and elucidate its functional implications. In this proposal, we aim to develop a suite of novel technologies for comprehensive structural and dynamic analyses of genomes, in two aspects: (1) the spatial interactions and higher-order organization of genomic DNA and (2) the functional organization of protein complexes driving the 3D folding of genomes. The new computational and experimental methods proposed herein integrate multiple experimental inputs and generate physical higher-order models of the 3D nuclear genome organization. Analysis of these models will yield new insights into the principles and structure/functions relationships of the genome's 3D organization in space and time. We have the following aims: (1) Develop technologies for mapping the relative spatial positions of genomic DNA in the nucleus: our focus will be on the three major technical barriers faced by all current mapping technologies, namely inefficient and potentially biased data acquisition, lack of temporal resolution, and missing higher-order contact information. (2) Develop technologies for deciphering the "Protein Code" of 3D genome organizations: we will employ a proven pipeline for the isolation of native protein complexes, but extensively optimized for the purpose of reading out the chromatin interactome surrounding each particular chromatin interacting region. (3) Develop technologies for modeling and analysis of 3D genome structures: we will develop an integrated platform for population-based modeling of 3D genome structures, and develop a series of computational tools to perform structure-function mapping on the 3D genomes. (4) Develop sold validation techniques for guiding the above technology innovations: we will develop a set of simple-to-implement and easy-to-interpret techniques to validate our novel technologies, and this techniques can be generally adopted by the community for similar validation purposes.

 描述：基因组的3D结构组织在基因表达和DNA复制等核功能中起着关键作用。生物学的下一个重大挑战之一是确定详细的3D基因组结构并阐明其功能意义。在这项提案中，我们的目标是开发一套新的技术，用于基因组的全面结构和动态分析，在两个方面：（1）基因组DNA的空间相互作用和高阶组织和（2）蛋白质复合物的功能组织驱动基因组的3D折叠。本文提出的新的计算和实验方法集成了多个实验输入，并生成3D核基因组组织的物理高阶模型。这些模型的分析将产生新的见解的原则和结构/功能关系的基因组的三维组织在空间和时间。我们的目标如下：（1）开发用于绘制基因组DNA在细胞核中的相对空间位置的技术：我们的重点将是所有当前绘制技术所面临的三个主要技术障碍，即效率低下和可能有偏见的数据获取，缺乏时间分辨率，以及缺少高阶联系信息。(2)开发用于破译3D基因组组织的“蛋白质密码”的技术：我们将采用经过验证的管道来分离天然蛋白质复合物，但为了阅读每个特定染色质相互作用区域周围的染色质相互作用组而进行了广泛优化。(3)开发三维基因组结构建模和分析技术：我们将开发一个基于群体的三维基因组结构建模的集成平台，并开发一系列计算工具来对三维基因组进行结构-功能映射。(4)开发用于指导上述技术创新的销售验证技术：我们将开发一套易于实现和易于解释的技术来验证我们的新技术，该技术可被社区普遍采用用于类似的验证目的。

项目成果

Quantitative imaging of chromatin decompaction in living cells.

• DOI: 10.1091/mbc.e17-11-0648
• 发表时间: 2018-07-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Dultz E;Mancini R;Polles G;Vallotton P;Alber F;Weis K
• 通讯作者: Weis K

Evaluating the role of the nuclear microenvironment in gene function by population-based modeling.

• DOI: 10.1038/s41594-023-01036-1
• 发表时间: 2023-08
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Yildirim, Asli;Hua, Nan;Boninsegna, Lorenzo;Zhan, Yuxiang;Polles, Guido;Gong, Ke;Hao, Shengli;Li, Wenyuan;Zhou, Xianghong Jasmine;Alber, Frank
• 通讯作者: Alber, Frank

Integrative genome modeling platform reveals essentiality of rare contact events in 3D genome organizations.

• DOI: 10.1038/s41592-022-01527-x
• 发表时间: 2022-08
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Boninsegna, Lorenzo;Yildirim, Asli;Polles, Guido;Quinodoz, Sofia A.;Finn, Elizabeth;Guttman, Mitchell;Zhou, Xianghong Jasmine;Alber, Frank;Zhan, Yuxiang
• 通讯作者: Zhan, Yuxiang

TopDom: an efficient and deterministic method for identifying topological domains in genomes.

• DOI: 10.1093/nar/gkv1505
• 发表时间: 2016-04-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Shin H;Shi Y;Dai C;Tjong H;Gong K;Alber F;Zhou XJ
• 通讯作者: Zhou XJ

Integrative approaches in genome structure analysis.

• DOI: 10.1016/j.str.2021.12.003
• 发表时间: 2022-01-06
• 期刊: Structure (London, England : 1993)
• 作者: Boninsegna L;Yildirim A;Zhan Y;Alber F
• 通讯作者: Alber F