Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes.
Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes.
复制标题
增强子调控网络在全球范围内将非编码乳腺癌基因座与癌症基因连接起来。
DOI：
10.1101/2023.11.20.567880
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Hon,GaryC
中科院分区：
文献类型：
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作者：
Wang,Yihan;Armendariz,Daniel;Wang,Lei;Zhao,Huan;Xie,Shiqi;Hon,GaryC
背景遗传学研究已将数千种增强子与乳腺癌(BC)联系起来。然而，绝大多数还没有得到功能上的描述。结果在这里，我们对3513个与乳腺癌相关的调控元件进行单细胞CRISPRi筛选，以测量这些区域对转录表型的影响。对两个乳腺癌细胞系中 >； 500,000个单细胞转录本的分析表明，BC相关增强子的干扰扰乱了乳腺癌基因程序。我们观察到与BC相关的增强子直接或间接调节癌症基因的表达。我们还发现了一对多和多对一的网络基序，其中增强子间接调节癌症基因。值得注意的是，多个BC相关增强子间接调节TP53。比较研究阐明了增强子在ER + 和ER − 细胞中的亚型特异性功能。最后，我们开发了pySpade软件包，以便于分析单细胞增强子筛查。结论总的来说，我们证明了增强子形成了连接基因组中癌症基因的调控网络，提供了对增强子在乳腺癌发展中的贡献的更全面的理解。
BackgroundGenetic studies have associated thousands of enhancers with breast cancer (BC). However, the vast majority have not been functionally characterized. Thus, it remains unclear how BC-associated enhancers contribute to cancer.ResultsHere, we perform single-cell CRISPRi screens of 3513 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of > 500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of BC-associated enhancers disrupts breast cancer gene programs. We observe BC-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple BC-associated enhancers indirectly regulate TP53. Comparative studies illustrate subtype specific functions between enhancers in ER + and ER − cells. Finally, we develop the pySpade package to facilitate analysis of single-cell enhancer screens.ConclusionsOverall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.