Section of Cancer Genomics, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, MD, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Neoplasia. 2019 Apr;21(4):401-412. doi: 10.1016/j.neo.2019.02.003. Epub 2019 Mar 22.
Chromosomal aneuploidy is a defining feature of carcinomas and results in tumor-entity specific genomic imbalances. For instance, most sporadic colorectal carcinomas carry extra copies of chromosome 7, an aneuploidy that emerges already in premalignant adenomas, and is maintained throughout tumor progression and in derived cell lines. A comprehensive understanding on how chromosomal aneuploidy affects nuclear organization and gene expression, i.e., the nucleome, remains elusive. We now analyzed a cell line established from healthy colon mucosa with a normal karyotype (46,XY) and its isogenic derived cell line that acquired an extra copy of chromosome 7 as its sole anomaly (47,XY,+7). We studied structure/function relationships consequent to aneuploidization using genome-wide chromosome conformation capture (Hi-C), RNA sequencing and protein profiling. The gain of chromosome 7 resulted in an increase of transcript levels of resident genes as well as genome-wide gene and protein expression changes. The Hi-C analysis showed that the extra copy of chromosome 7 is reflected in more interchromosomal contacts between the triploid chromosomes. Chromatin organization changes are observed genome-wide, as determined by changes in A/B compartmentalization and topologically associating domain (TAD) boundaries. Most notably, chromosome 4 shows a profound loss of chromatin organization, and chromosome 14 contains a large A/B compartment switch region, concurrent with resident gene expression changes. No changes to the nuclear position of the additional chromosome 7 territory were observed when measuring distances of chromosome painting probes by interphase FISH. Genome and protein data showed enrichment in signaling pathways crucial for malignant transformation, such as the HGF/MET-axis. We conclude that a specific chromosomal aneuploidy has profound impact on nuclear structure and function, both locally and genome-wide. Our study provides a benchmark for the analysis of cancer nucleomes with complex karyotypes.
染色体非整倍性是癌的一个特征，导致肿瘤实体特异性的基因组失衡。例如，大多数散发性结直肠癌携带额外的染色体 7 拷贝，这种非整倍性在癌前腺瘤中就已经出现，并在肿瘤进展和衍生的细胞系中得到维持。对于染色体非整倍性如何影响核组织和基因表达，即核组，我们仍然知之甚少。我们现在分析了一个来自健康结肠黏膜的细胞系，其核型正常（46,XY），及其同源衍生的细胞系，该细胞系获得了额外的染色体 7 拷贝作为其唯一的异常（47,XY,+7）。我们使用全基因组染色体构象捕获（Hi-C）、RNA 测序和蛋白质谱分析研究了非整倍化后结构/功能关系。染色体 7 的获得导致驻留基因的转录水平以及全基因组基因和蛋白质表达的变化增加。Hi-C 分析表明，额外的染色体 7 拷贝反映在三倍体染色体之间更多的染色体间接触。染色质组织的变化是全基因组范围内观察到的，这是由 A/B 区室化和拓扑关联域（TAD）边界的变化决定的。最值得注意的是，染色体 4 显示出染色质组织的严重丧失，而染色体 14 包含一个大的 A/B 区室转换区域，同时伴随着驻留基因表达的变化。在通过间期 FISH 测量染色体染色探针的距离时，没有观察到额外的染色体 7 区域的核位置发生变化。基因组和蛋白质数据显示，与恶性转化相关的信号通路，如 HGF/MET 轴，富集。我们得出结论，特定的染色体非整倍性对局部和全基因组的核结构和功能都有深远的影响。我们的研究为分析具有复杂核型的癌症核组提供了一个基准。
