The role of histone modifications is poorly characterized in breast cancer, especially within the major subtypes. While epigenetic modifications may enhance the adaptability of a cell to both therapy and the surrounding environment, the mechanisms by which this is accomplished remains unclear. In this study we focus on the HER2 subtype and investigate two histone trimethylations that occur on the histone 3; the trimethylation located at lysine 4 (H3K4me3) found in active promoters and the trimethylation located at lysine 27 (H3K27me3) that correlates with gene repression. A bivalency state is the result of the co-presence of these two marks at the same promoter. In this study we investigated the relationship between these histone modifications in promoter regions and their proximal gene expression in HER2+ breast cancer cell lines. In addition, we assessed these patterns with respect to the presence or absence of the estrogen receptor (ER). To do this, we utilized ChIP-seq and matching RNA-seq from publicly available data for the AU565, SKBR3, MB361 and UACC812 cell lines. In order to visualize these relationships, we used KEGG pathway enrichment analysis, and Kaplan-Meyer plots. We found that the correlation between the three types of promoter trimethylation statuses (H3K4me3, H3K27me3 or both) and the expression of the proximal genes was highly significant overall, while roughly a third of all genes are regulated by this phenomenon. We also show that there are several pathways related to cancer progression and invasion that are associated with the bivalent status of the gene promoters, and that there are specific differences between ER+ and ER- HER2+ breast cancer cell lines. These specific differences that are differentially trimethylated are also shown to be differentially expressed in patient samples. One of these genes, HIF1AN, significantly correlates with patient outcome. This study highlights the importance of looking at epigenetic markings at a subtype specific level by characterizing the relationship between the bivalent promoters and gene expression. This provides a deeper insight into a mechanism that could lead to future targets for treatment and prognosis, along with oncogenesis and response to therapy of HER2+ breast cancer patients.

中文翻译：

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对 HER2+ 乳腺癌细胞系中 H3K4me3 和 H3K27me3 二价启动子的分析揭示了取决于雌激素受体状态的变化，并且与基因表达显着相关。

组蛋白修饰在乳腺癌中的作用尚不清楚，尤其是在主要亚型中。虽然表观遗传修饰可能增强细胞对治疗和周围环境的适应性，但实现这一目标的机制仍不清楚。在本研究中，我们重点关注 HER2 亚型，并研究组蛋白 3 上发生的两种组蛋白三甲基化；活性启动子中发现的赖氨酸 4 (H3K4me3) 处的三甲基化以及与基因抑制相关的赖氨酸 27 (H3K27me3) 处的三甲基化。二价状态是这两个标记在同一启动子处共同存在的结果。在这项研究中，我们研究了 HER2+ 乳腺癌细胞系中启动子区域的这些组蛋白修饰与其近端基因表达之间的关系。此外，我们还根据雌激素受体 (ER) 的存在或不存在来评估这些模式。为此，我们利用 ChIP-seq 和来自 AU565、SKBR3、MB361 和 UACC812 细胞系公开数据的匹配 RNA-seq。为了可视化这些关系，我们使用了 KEGG 通路富集分析和 Kaplan-Meyer 图。我们发现三种类型的启动子三甲基化状态（H3K4me3、H3K27me3 或两者）与近端基因的表达之间的相关性总体上非常显着，而大约三分之一的基因受这种现象的调节。我们还表明，有几种与癌症进展和侵袭相关的途径与基因启动子的二价状态相关，并且 ER+ 和 ER-HER2+ 乳腺癌细胞系之间存在特定差异。这些差异三甲基化的特定差异也显示在患者样本中差异表达。其中一个基因 HIF1AN 与患者的预后显着相关。这项研究强调了通过表征二价启动子和基因表达之间的关系在亚型特异性水平上观察表观遗传标记的重要性。这提供了对一种机制的更深入的了解，该机制可能导致未来的治疗和预后目标，以及 HER2+ 乳腺癌患者的肿瘤发生和治疗反应。