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Computational methods to identify neo-TADs and enhancer-hijacking in rearranged genomes

识别重排基因组中新 TAD 和增强子劫持的计算方法

基本信息

批准号：
10610878
负责人：
Feng Yue
金额：
$ 40.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-07 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610878
关键词：
3-Dimensional ATAC-seq Acute Myelocytic Leukemia Acute T Cell Leukemia Algorithms CRISPR/Cas technology Cancer cell line Cell Line Cell Proliferation Cells ChIP-seq Chromatin Chromosome 3 Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Code Communities Computer software Computing Methodologies Copy Number Polymorphism Data Data Set Disease Distal EVI1 gene Enhancers Environment Epigenetic Process Event Gene Expression Regulation Genes Genetic Genome Genomics Hi-C Human Cell Line Human Genome K-562 Knock-out Limb structure Malignant Neoplasms Maps Measures Methods Modeling Oncogenes Output Pathogenesis Patients Phenotype Proto-Oncogenes Publishing Regulatory Element Reporting Resolution Resources Role Sampling Series Source Structure Systematic Bias Testing Untranslated RNA Up-Regulation Validation Variant cancer cell cancer genome cancer genomics cancer type cell motility cell type chromosome fusion disease phenotype epigenomics experimental study genome-wide human disease malformation mammalian genome novel promoter restraint software development transcriptome sequencing tumor progression

项目摘要

PROJECT SUMMARY / ABSTRACT Structural variations (SVs), including inversions, deletions, duplications, and translocations, are prevalent in cancer and other diseases. It has been shown recently that SVs can disrupt the 3D genome structure and directly contribute to pathogenesis. For example, in T-cell acute lymphoblastic leukemia, deletion of a TAD boundary disrupted the insulated chromatin domains and activates proto-oncogenes. Two main consequences of SVs on 3D genome structures are the formations of “neo-TADs” and “enhancer-hijacking.” Neo-TADs refers to the scenarios when a SV event leads to the formation new chromatin domains, particularly in the cancer genomes, while enhancer-hijacking means when a SV event rearranges the cancer genome and juxtaposes an enhancer to the proximity of an oncogene. 3D genome organization has been shown to be essential in proper gene regulation and cell fate. Previous studies have shown that mammalian genomes are organized in megabase pair topologically associating domains (TADs). Genes located within the same TADs tend to be co-regulated and the functions of enhancers are usually restrained by TADs boundaries. Both genetic and epigenetic alteration of TADs boundaries can lead to gene misregulation and severe human diseases. To study the 3D genome organization, Hi-C is by far the most popular method, as it can measure chromatin interactions genome-wide. It facilitates the original discovery of TADs and many enhancer-promoter interactions. Recently, Hi-C has been applied to tens of cancer cell lines and a small number of patient samples. However, to our knowledge, no methods exist that can identify neo-TADs or enhancer-hijacking events using the Hi-C interaction data in cancer cells. Therefore, in this study, we propose the following aims: 1) Develop computational method to detect neo-TADs in cancer genome; 2) Develop computational method to detect chromatin interactions in cancer genomes; 3) Perform validation experiments for the hijacked enhancers by CRISPR/Cas9 and investigate their effect on target genes and cell phenotypes.

项目概要/摘要结构变异 (SV)，包括倒位、缺失、重复和易位，多见于癌症和其他疾病。最近表明 SV 可以破坏 3D 基因组结构并直接参与发病机制。例如，在 T 细胞急性淋巴细胞白血病中，缺失 TAD 边界的破坏破坏了绝缘的染色质结构域并激活了原癌基因。主要有两个 SV 对 3D 基因组结构的影响是“新 TAD”和“增强子劫持”的形成。 Neo-TAD 是指 SV 事件导致新染色质结构域形成的情况，特别是在癌症基因组中，增强子劫持意味着 SV 事件重新排列癌症基因组并将增强子与癌基因附近并置。 3D 基因组组织已被证明对于正确的基因调控和细胞命运至关重要。先前的研究表明，哺乳动物基因组在拓扑上以兆碱基对的形式组织关联域 (TAD)。位于相同 TAD 内的基因往往是共同调控的，并且其功能增强子通常受到 TAD 边界的限制。 TAD 的遗传和表观遗传改变边界可能导致基因失调和严重的人类疾病。研究 3D 基因组 Hi-C 是迄今为止最流行的方法，因为它可以测量全基因组范围内的染色质相互作用。它促进了 TAD 和许多增强子-启动子相互作用的最初发现。近日，Hi-C 适用于数十种癌细胞系和少量患者样本。然而，据我们所知，没有存在可以使用 Hi-C 相互作用数据来识别 neo-TAD 或增强子劫持事件的方法癌细胞。因此，在本研究中，我们提出以下目标：1）开发计算方法来检测癌症基因组中的新 TAD； 2) 开发检测癌症中染色质相互作用的计算方法基因组； 3) 对CRISPR/Cas9劫持的增强子进行验证实验并进行研究它们对靶基因和细胞表型的影响。