Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors
Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors
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DOI：
10.3390/epigenomes3020011
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发表时间：
2019-06-01
期刊：
影响因子：
2.5
通讯作者：
Frietze, Seth
中科院分区：
文献类型：
--
作者：
Gerrard, Diana L.;Boyd, Joseph R.;Frietze, Seth
表观遗传结构域的扩展已经成为不同细胞类型的区别表观基因组表型。特别是，H3 K27 ac-和H3 K4 me 3-标记元件的簇，分别称为超级增强子和宽H3 K4 me 3结构域，已经与细胞身份和疾病状态相关联。在这里，我们表征了来自不同胰腺导管腺癌（PDAC）细胞系的代表不同组织学等级的广泛域。我们的综合基因组分析发现，不同PDAC等级的人源细胞系模型表现出与基因表达模式相关的特征性广泛表观遗传特征，这些特征可预测患者预后并提供对胰腺癌细胞身份的了解。特别是，我们发现，标记重叠低级别广泛域的基因对应于上皮表型，并保持作为患者分层的标志物的潜力。我们进一步利用ChIP-seq来比较组蛋白乙酰转移酶（HAT）抑制剂的作用，以检测组蛋白乙酰化和甲基化水平的总体变化。我们发现HAT抑制剂影响胰腺癌细胞的某些广泛领域。总的来说，我们的结果揭示了广泛的结构域在不同PDAC等级的细胞中的潜在作用，并证明了特定广泛的表观基因组结构域对表观遗传抑制剂的可塑性。
The spreading of epigenetic domains has emerged as a distinguishing epigenomic phenotype for diverse cell types. In particular, clusters of H3K27ac- and H3K4me3-marked elements, referred to as super-enhancers, and broad H3K4me3 domains, respectively, have been linked to cell identity and disease states. Here, we characterized the broad domains from different pancreatic ductal adenocarcinoma (PDAC) cell lines that represent distinct histological grades. Our integrative genomic analysis found that human derived cell line models for distinct PDAC grades exhibit characteristic broad epigenetic features associated with gene expression patterns that are predictive of patient prognosis and provide insight into pancreatic cancer cell identity. In particular, we find that genes marked by overlapping Low-Grade broad domains correspond to an epithelial phenotype and hold potential as markers for patient stratification. We further utilize ChIP-seq to compare the effects of histone acetyltransferase (HAT) inhibitors to detect global changes in histone acetylation and methylation levels. We found that HAT inhibitors impact certain broad domains of pancreatic cancer cells. Overall, our results reveal potential roles for broad domains in cells from distinct PDAC grades and demonstrate the plasticity of particular broad epigenomic domains to epigenetic inhibitors.