National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan 430070, China; Hubei Key Laboratory of Agricultural Bioinformatics and Hubei Engineering Technology Research Center of Agricultural Big Data, 3D Genomics Research Center, Huazhong Agricultural University, Wuhan 430070, China.
National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan 430070, China.
Genomics Proteomics Bioinformatics. 2023 Jun;21(3):573-588. doi: 10.1016/j.gpb.2023.01.004. Epub 2023 Jan 23.
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.
对肺癌基因组的研究对于开发肺癌治疗方法是必不可少的。全基因组重测序、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认识。然而，肺癌中长程染色质相互作用的失调仍描述不足。为了更好地了解肺癌基因组的三维（3D）基因组相互作用特征，我们使用 A549 细胞系作为模型系统，并使用长读长染色质相互作用分析通过末端标签测序（ChIA-PET）生成与 RNA 聚合酶 II（RNAPII）、CCCTC 结合因子（CTCF）、EZH2 和组蛋白 3 赖氨酸 27 三甲基化（H3K27me3）相关的高分辨率染色质相互作用。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，它们在基因组上的分布与与 RNAPII 相关的分布不同且互补。与癌症相关的基因与染色质相互作用高度富集，并且 A549 细胞系特有的染色质相互作用与癌基因和肿瘤抑制基因相关，例如 FOXO4 上的额外抑制性相互作用和 NF1 和 RNF135 之间的启动子-启动子相互作用。与染色质相互作用相关的锚点的敲除逆转了与癌症相关的基因的失调，表明染色质相互作用对于肺癌相关基因的正确表达是必不可少的。这些发现展示了肺癌基因组的 3D 景观和基因调控关系。
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