Mapping Multi-factor-mediated Chromatin Interactions to Assess Dysregulation of Lung Cancer-related Genes.

IF 11.5 2区 生物学 Q1 GENETICS & HEREDITY Genomics, Proteomics & Bioinformatics Pub Date : 2023-06-01 Epub Date: 2023-01-23 DOI:10.1016/j.gpb.2023.01.004
Yan Zhang, Jingwen Zhang, Wei Zhang, Mohan Wang, Shuangqi Wang, Yao Xu, Lun Zhao, Xingwang Li, Guoliang Li
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Abstract

Studies on the lung cancer genome are indispensable for developing a cure for lung cancer. Whole-genome resequencing, genome-wide association studies, and transcriptome sequencing have greatly improved our understanding of the cancer genome. However, dysregulation of long-range chromatin interactions in lung cancer remains poorly described. To better understand the three-dimensional (3D) genomic interaction features of the lung cancer genome, we used the A549 cell line as a model system and generated high-resolution chromatin interactions associated with RNA polymerase II (RNAPII), CCCTC-binding factor (CTCF), enhancer of zeste homolog 2 (EZH2), and histone 3 lysine 27 trimethylation (H3K27me3) using long-read chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Analysis showed that EZH2/H3K27me3-mediated interactions further repressed target genes, either through loops or domains, and their distributions along the genome were distinct from and complementary to those associated with RNAPII. Cancer-related genes were highly enriched with chromatin interactions, and chromatin interactions specific to the A549 cell line were associated with oncogenes and tumor suppressor genes, such as additional repressive interactions on FOXO4 and promoter-promoter interactions between NF1 and RNF135. Knockout of an anchor associated with chromatin interactions reversed the dysregulation of cancer-related genes, suggesting that chromatin interactions are essential for proper expression of lung cancer-related genes. These findings demonstrate the 3D landscape and gene regulatory relationships of the lung cancer genome.

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绘制多因子介导的染色质相互作用以评估肺癌相关基因的失调。
对肺癌癌症基因组的研究对于开发癌症的治疗方法是必不可少的。全基因组重新测序、全基因组关联研究和转录组测序极大地提高了我们对癌症基因组的理解。然而,癌症中长程染色质相互作用的失调仍不清楚。为了更好地理解癌症基因组的三维(3D)基因组相互作用特征,我们使用A549细胞系作为模型系统,并产生了与RNA聚合酶II(RNAPII)、CCCTC-结合因子(CTCF)、齐斯特同源物2(EZH2)增强子、,组蛋白3赖氨酸27三甲基化(H3K27me3)。分析表明,EZH2/H3K27me3介导的相互作用通过环或结构域进一步抑制靶基因,并且它们在基因组中的分布与RNAPII相关的分布不同并互补。癌症相关基因与染色质相互作用高度富集,A549细胞系特异性的染色质相互关系与致癌基因和肿瘤抑制基因相关,例如对FOXO4的额外抑制性相互作用以及NF1和RNF135之间的启动子-启动子相互作用。敲除与染色质相互作用相关的锚逆转了癌症相关基因的失调,这表明染色质的相互作用对于肺癌相关基因的正确表达至关重要。这些发现证明了癌症基因组的三维景观和基因调控关系。
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来源期刊
Genomics, Proteomics & Bioinformatics
Genomics, Proteomics & Bioinformatics Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
14.30
自引率
4.20%
发文量
844
审稿时长
61 days
期刊介绍: Genomics, Proteomics and Bioinformatics (GPB) is the official journal of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China. It aims to disseminate new developments in the field of omics and bioinformatics, publish high-quality discoveries quickly, and promote open access and online publication. GPB welcomes submissions in all areas of life science, biology, and biomedicine, with a focus on large data acquisition, analysis, and curation. Manuscripts covering omics and related bioinformatics topics are particularly encouraged. GPB is indexed/abstracted by PubMed/MEDLINE, PubMed Central, Scopus, BIOSIS Previews, Chemical Abstracts, CSCD, among others.
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