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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.

项目摘要/摘要