Noncoding transcription is a defining feature of active enhancers, linking transcription factor (TF) binding to the molecular mechanisms controlling gene expression. To determine the relationship between enhancer activity and biological outcomes in breast cancers, we profiled the transcriptomes (using GRO-seq and RNA-seq) and epigenomes (using ChIP-seq) of 11 different human breast cancer cell lines representing five major molecular subtypes of breast cancer, as well as two immortalized ("normal") human breast cell lines. In addition, we developed a robust and unbiased computational pipeline that simultaneously identifies putative subtype-specific enhancers and their cognate TFs by integrating the magnitude of enhancer transcription, TF mRNA expression levels, TF motif P-values, and enrichment of H3K4me1 and H3K27ac. When applied across the 13 different cell lines noted above, the Total Functional Score of Enhancer Elements (TFSEE) identified key breast cancer subtype-specific TFs that act at transcribed enhancers to dictate gene expression patterns determining growth outcomes, including Forkhead TFs, FOSL1, and PLAG1. FOSL1, a Fos family TF, (1) is highly enriched at the enhancers of triple negative breast cancer (TNBC) cells, (2) acts as a key regulator of the proliferation and viability of TNBC cells, but not Luminal A cells, and (3) is associated with a poor prognosis in TNBC breast cancer patients. Taken together, our results validate our enhancer identification pipeline and reveal that enhancers transcribed in breast cancer cells direct critical gene regulatory networks that promote pathogenesis.

中文翻译：

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增强子转录揭示了控制乳腺癌发病机制的亚型特异性基因表达程序。

非编码转录是活性增强子的定义特征，它将转录因子（TF）结合到控制基因表达的分子机制上。为了确定乳腺癌中增强子活性与生物学结果之间的关系，我们分析了代表5种主要分子亚型的11种不同人类乳腺癌细胞系的转录组（使用GRO-seq和RNA-seq）和表观基因组（使用ChIP-seq）。乳腺癌以及两种永生化（“正常”）人乳腺癌细胞系。此外，我们开发了一个健壮且无偏的计算管道，可通过整合增强子转录的幅度，TF mRNA表达水平，TF基序P值以及H3K4me1和H3K27ac的富集，同时鉴定推定的亚型特异性增强子及其同源TF。当在上述13种不同的细胞系中使用时，增强子元素总功能评分（TFSEE）确定了关键的乳腺癌亚型特异性TF，它们作用于转录的增强子，决定了决定生长结果的基因表达模式，包括Forkhead TF，FOSL1和PLAG1。FOSL1是一个Fos家族TF，（1）在三阴性乳腺癌（TNBC）细胞的增强子中高度富集，（2）充当TNBC细胞而非Luminal A细胞增殖和活力的关键调节剂，并且（3）与TNBC乳腺癌患者预后不良有关。综上所述，我们的结果验证了我们的增强子识别流程，并揭示了在乳腺癌细胞中转录的增强子指导着促进发病机理的关键基因调控网络。增强子元素的总功能评分（TFSEE）确定了关键的乳腺癌亚型特异性TF，它们可作用于转录的增强子，从而决定决定生长结果的基因表达模式，包括Forkhead TF，FOSL1和PLAG1。FOSL1是一个Fos家族TF，（1）在三阴性乳腺癌（TNBC）细胞的增强子中高度富集，（2）充当TNBC细胞而非Luminal A细胞增殖和活力的关键调节剂，并且（3）与TNBC乳腺癌患者预后不良有关。综上所述，我们的结果验证了我们的增强子识别流程，并揭示了在乳腺癌细胞中转录的增强子指导着促进发病机理的关键基因调控网络。增强子元素的总功能评分（TFSEE）确定了关键的乳腺癌亚型特异性TF，它们可作用于转录的增强子，从而决定决定生长结果的基因表达模式，包括Forkhead TF，FOSL1和PLAG1。FOSL1是一个Fos家族TF，（1）在三阴性乳腺癌（TNBC）细胞的增强子中高度富集，（2）充当TNBC细胞而非Luminal A细胞增殖和活力的关键调节剂，并且（3）与TNBC乳腺癌患者预后不良有关。综上所述，我们的结果验证了我们的增强子识别流程，并揭示了在乳腺癌细胞中转录的增强子指导着促进发病机理的关键基因调控网络。