Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
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DOI：
10.1038/s41588-019-0564-y
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发表时间：
2020-02-05
期刊：
影响因子：
30.8
通讯作者：
Zhang, Cheng-Zhong
中科院分区：
文献类型：
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作者：
Akdemir, Kadir C.;Le, Victoria T.;Zhang, Cheng-Zhong
染色质折叠成连续的层来组织线性DNA。在相同的拓扑结构相关域（TADs）内的基因表现出相似的表达和组蛋白修饰概况，并且分隔不同域的边界在加强这些特征的稳定性方面具有重要作用。事实上，人类癌症中的结构域破坏可能导致基因表达的失调。然而，人类癌症中结构域破坏的频率仍不清楚。在这里，作为国际癌症基因组联盟（ICGC）和癌症基因组图谱（TCGA）的泛癌症全基因组分析（PCAWG）联盟的一部分，该联盟汇总了来自38种肿瘤类型的2，658种癌症的全基因组测序数据，我们分析了288，457个体细胞结构变异（SV），以了解SV在TAD中的分布和影响。值得注意的是，SV可以导致离散的TAD融合，并且复杂的重排显著改变癌症基因组中的染色质折叠图谱。值得注意的是，只有14%的边界缺失导致附近基因表达的变化超过2倍。一项泛癌基因组分析报告了结构变异对染色质结构域（TADs）的影响。大多数干扰不会导致附近基因表达的明显变化。
Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.