Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes.
Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes.
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组蛋白 H3 赖氨酸 4 乙酰化和甲基化动态定义乳腺癌亚型。
DOI：
10.18632/oncotarget.6922
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Stein GS
中科院分区：
文献类型：
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作者：
Messier TL;Gordon JA;Boyd JR;Tye CE;Browne G;Stein JL;Lian JB;Stein GS
乳腺癌的发生和发展与改变细胞正常编程的遗传和表观遗传变化有关。DNA和组蛋白的表观遗传修饰有助于染色质结构，导致基因表达的激活或抑制。已证明癌细胞中的几种表观遗传途径高度失调。靶向特异性组蛋白修饰代表了预防致癌转化、肿瘤生长或转移的可行策略。组蛋白H3赖氨酸4的甲基化已被广泛研究，并显示标记基因的表达;然而，该残基也可以被乙酰化，这种改变的具体功能鲜为人知。为了确定组蛋白H3甲基化（H3 K4 me 3）和乙酰化（H3 K4 ac）在乳腺癌中的相对作用，我们使用全基因组ChIP-Seq方法确定了正常样（MCF 10A），转化（MCF 7）和转移（MDA-MB-231）细胞中富集两种标记的基因组区域。我们的数据显示，H3 K4 ac的全基因组获得与早期和晚期乳腺癌细胞表型相关，而H3 K4 me 3的获得主要与晚期癌细胞相关。H3 K4 ac的富集在与癌症相关的表型性状（如雌激素反应和上皮-间充质转化途径）相关的基因的启动子处过度表达。我们的研究结果强调了H3 K4 ac在预测与转化早期阶段相关的表观遗传变化方面的重要作用。此外，我们的数据为理解与已知乳腺癌相关致癌途径相关的表观遗传特征提供了宝贵的资源。
The onset and progression of breast cancer are linked to genetic and epigenetic changes that alter the normal programming of cells. Epigenetic modifications of DNA and histones contribute to chromatin structure that result in the activation or repression of gene expression. Several epigenetic pathways have been shown to be highly deregulated in cancer cells. Targeting specific histone modifications represents a viable strategy to prevent oncogenic transformation, tumor growth or metastasis. Methylation of histone H3 lysine 4 has been extensively studied and shown to mark genes for expression; however this residue can also be acetylated and the specific function of this alteration is less well known. To define the relative roles of histone H3 methylation (H3K4me3) and acetylation (H3K4ac) in breast cancer, we determined genomic regions enriched for both marks in normal-like (MCF10A), transformed (MCF7) and metastatic (MDA-MB-231) cells using a genome-wide ChIP-Seq approach. Our data revealed a genome-wide gain of H3K4ac associated with both early and late breast cancer cell phenotypes, while gain of H3K4me3 was predominantly associated with late stage cancer cells. Enrichment of H3K4ac was over-represented at promoters of genes associated with cancer-related phenotypic traits, such as estrogen response and epithelial-to-mesenchymal transition pathways. Our findings highlight an important role for H3K4ac in predicting epigenetic changes associated with early stages of transformation. In addition, our data provide a valuable resource for understanding epigenetic signatures that correlate with known breast cancer-associated oncogenic pathways.