Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations.

中文翻译：

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增强子突变调节化疗引起的骨髓抑制的严重程度。

非小细胞肺癌通常在晚期才被诊断出来，许多患者仍在接受经典化疗。化疗的非选择性常常导致严重的骨髓抑制。先前的研究表明，蛋白质编码突变不能完全解释骨髓抑制的倾向。在这里，我们研究增强子突变在骨髓抑制易感性中的可能作用。我们制作了用卡铂或吉西他滨处理的三种血液干细胞样细胞系的转录组和启动子相互作用图谱（使用 HiCap）。利用公开可用的增强子数据集，我们使用表观遗传 CRISPR 技术在计算机和活细胞中验证了 HiCap 结果。我们还开发了一种用于相互作用组分析和差异相互作用基因检测的网络方法。与批量水平的差异基因表达分析相比，差异相互作用分析提供了有关骨髓抑制相关基因和途径的更多信息。此外，我们发现差异相互作用基因的增强子高度富集与不同水平骨髓抑制相关的变异。总而言之，我们的工作代表了用于非编码突变功能注释的综合转录组和基因调控数据集分析的突出例子。