小柯机器人

美国索尔克研究所Jesse R. Dixon小组发现，结构变异驱动癌症中背景依赖的癌基因激活。2022年12月7日，《自然》杂志在线发表了这项成果。

研究人员表示，高阶染色质结构对于远端调控序列对基因的调控非常重要。改变三维（3D）基因组组织的结构性变异（SV）可以导致增强子-启动子的重构和人类疾病，特别是在癌症方面。然而，只有少数SV与基因表达的改变有关，而且目前仍不清楚为什么某些SV会导致远端基因表达的改变，而其他SV则不会。

为了解决这些问题，研究人员使用了基因组分析和基因组工程的组合来确定癌症中三维基因组结构反复变化的部位，并确定特定重排对致癌基因激活的影响。通过分析92个癌症细胞系和患者样本的Hi-C数据，研究人员确定了受三维基因组结构反复改变影响的位点，包括MYC、TERT和CCND1等致癌基因。通过使用CRISPR-Cas9基因组工程来产生新的SV，研究人员表明，可以通过使用“逐一接触的活性”模型来预测致癌基因的活性，该模型考虑了伙伴区域染色质接触和增强子活性。然而，逐个接触的活性模型只能预测基因组中特定的基因亚群，这表明不同类别的基因参与远端调控元件的不同调节模式。这些结果表明，改变三维基因组组织的SV在癌症基因组中广泛存在，并初步说明了SV对肿瘤基因激活后果的预测规则。

附：英文原文

Title: Structural variants drive context-dependent oncogene activation in cancer

Author: Xu, Zhichao, Lee, Dong-Sung, Chandran, Sahaana, Le, Victoria T., Bump, Rosalind, Yasis, Jean, Dallarda, Sofia, Marcotte, Samantha, Clock, Benjamin, Haghani, Nicholas, Cho, Chae Yun, Akdemir, Kadir C., Tyndale, Selene, Futreal, P. Andrew, McVicker, Graham, Wahl, Geoffrey M., Dixon, Jesse R.

Issue&Volume: 2022-12-07

Abstract: Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences1,2. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer–promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analysing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT and CCND1. By using CRISPR–Cas9 genome engineering to generate de novo SVs, we show that oncogene activity can be predicted by using ‘activity-by-contact’ models that consider partner region chromatin contacts and enhancer activity. However, activity-by-contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that SVs that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of SVs on oncogene activation.

DOI: 10.1038/s41586-022-05504-4

Source: https://www.nature.com/articles/s41586-022-05504-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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