Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells
Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells
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DOI：
10.1038/onc.2012.477
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发表时间：
2013-09-19
期刊：
影响因子：
8
通讯作者：
Brown, R.
中科院分区：
文献类型：
--
作者：
Chapman-Rothe, N.;Curry, E.;Brown, R.
在胚胎干细胞（ES）中，含有H3 K4 me 3和H3 K27 me 3的二价染色质结构域标记沉默发育基因，同时使它们在分化后保持激活状态。我们已经确定了与H3 K27 me 3和H3 K4 me 3标记在高级别卵巢浆液性肿瘤的转录起始位点相关的基因集，并研究了它们与表观遗传沉默和恶性进展的关系。这揭示了新的沉默的二价标记基因，以前没有描述的ES细胞，这是显着富集PI 3 K（P < 10（-7））和TGF-β信号通路（P < 10（-5））。我们将组蛋白标记的基因组与8个正常输卵管和499个高度浆液性恶性卵巢样本的基因表达组进行了匹配。这揭示了恶性组织中H3 K27 me 3和二价基因组的基因表达显著降低。然后，我们将H3 K27 me 3和二价基因组与卵巢肿瘤“干细胞样”维持细胞与非维持细胞的基因表达数据相关联。这表明在肿瘤维持细胞中H3 K27 me 3和二价基因组的表达显著降低。相似地，相匹配的化疗敏感和化疗耐药卵巢细胞系的比较显示，与化疗敏感细胞系相比，化疗耐药细胞系中H3 K27 me 3/二价标记基因的表达显著较低。我们的分析支持这样的假设，即二价标记与卵巢癌的表观遗传沉默有关。然而，它也表明，额外的肿瘤特异性二价标记，在ES细胞中已知的，存在于肿瘤中，并可能影响随后的耐药性和肿瘤进展的发展。
In embryonic stem (ES) cells, bivalent chromatin domains containing H3K4me3 and H3K27me3 marks silence developmental genes, while keeping them poised for activation following differentiation. We have identified gene sets associated with H3K27me3 and H3K4me3 marks at transcription start sites in a high-grade ovarian serous tumour and examined their association with epigenetic silencing and malignant progression. This revealed novel silenced bivalent marked genes, not described previously for ES cells, which are significantly enriched for the PI3K (P < 10(-7)) and TGF-beta signalling pathways (P < 10(-5)). We matched histone marked gene sets to gene expression sets of eight normal fallopian tubes and 499 high-grade serous malignant ovarian samples. This revealed a significant decrease in gene expression for the H3K27me3 and bivalent gene sets in malignant tissue. We then correlated H3K27me3 and bivalent gene sets to gene expression data of ovarian tumour 'stem cell-like' sustaining cells versus non-sustaining cells. This showed a significantly lower expression for the H3K27me3 and bivalent gene sets in the tumour-sustaining cells. Similarly, comparison of matched chemo-sensitive and chemo-resistant ovarian cell lines showed a significantly lower expression of H3K27me3/bivalent marked genes in the chemo-resistant compared with the chemo-sensitive cell line. Our analysis supports the hypothesis that bivalent marks are associated with epigenetic silencing in ovarian cancer. However it also suggests that additional tumour specific bivalent marks, to those known in ES cells, are present in tumours and may potentially influence the subsequent development of drug resistance and tumour progression.