Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain
Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain
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DOI：
10.1186/s12920-020-0695-0
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发表时间：
2020-03-06
影响因子：
2.7
通讯作者：
Nguyen, Don X.
中科院分区：
文献类型：
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作者：
Cai, Wesley L.;Greer, Celeste B.;Nguyen, Don X.
背景很少有体细胞突变与乳腺癌转移有关，而原发肿瘤之间的转录组差异与转移发生率相关，特别是肺和脑转移。然而，表观基因组的改变和转录因子（TF），这些变化的基础仍然不清楚。方法为了鉴定这些，我们对MDA-MB-231细胞系及其脑（BrM 2）和肺（LM 2）转移亚群进行了RNA-seq、染色质免疫沉淀和测序（ChIP-seq）和使用测序（ATAC-seq）的转座酶可降解染色质测定。我们结合了来自TCGA的ATAC-seq数据来评估转移性开放染色质特征，以及来自人类转移性数据集的基因表达数据来提名转录因子生物标志物。结果我们的综合表观基因组学分析发现，肺和脑转移细胞表现出共同的和独特的活性染色质的签名。值得注意的是，转移性亚群表现出启动子和增强子的激活增加。我们还将这些数据与染色体构象捕获结合ChIP-seq（HiChIP）衍生的增强子-启动子相互作用来预测增强子控制的途径改变。我们发现，增强子的变化与LM 2中的内皮细胞迁移和BrM 2中的上皮细胞增殖的负调控相关。启动子的变化与LM 2中的脉管系统发育和BrM 2中的嗜同性细胞粘附相关。使用ATAC-seq，我们确定了转移开放染色质特征，该特征在基底样和HER 2富集的乳腺癌亚型中升高，并与人类样本中的预后较差相关。我们进一步发现了与转移细胞的开放染色质景观相关的TF，其表达与转移风险相关。虽然这些TF中的一些与原发性乳腺肿瘤亚型相关，但其他TF更具体地与肺或脑转移相关。结论：我们确定了转移到肺和脑的乳腺癌细胞的独特表观基因组特性。我们还证明了活性染色质位点的特征与预后不良的人乳腺癌亚型部分相关，并且特定的TF可以独立区分肺和脑复发。
Background Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.