Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China.
Nat Commun. 2021 Sep 13;12(1):5318. doi: 10.1038/s41467-021-25670-9.
Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.
鉴定转录因子（TFs）的 DNA 结合被调节易感基因的遗传变异改变，对于理解疾病发病机制中的转录失调至关重要。在这里，我们开发了一个统计框架来分析广泛的 ChIP-seq 和 GWAS 数据，并鉴定出 22 个与乳腺癌风险相关的 TF。我们发现，通过分析 TF-DNA 结合的遗传变异，FOXA1 与 ESR1 和 E2F1 等共同因子的相互作用，以及 TF 与染色质特征（即增强子）的相互作用，在乳腺癌易感性中起着关键作用。使用这 22 个 TF 占据的遗传变异，对全转录组关联分析鉴定出 52 个先前未报道的乳腺癌易感基因，其中包括来自乳腺相关细胞系功能筛选的证据表明具有必需性的 7 个基因。我们表明，FOXA1 和共同因子形成了一个核心 TF 转录网络，调节易感基因。我们的研究结果为乳腺癌易感性相关的 TF-DNA 结合（特别是 FOXA1）的遗传变异提供了更多的见解。
