Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells
Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells
复制标题
多价表观遗传标记赋予卵巢癌细胞微环境响应的表观遗传可塑性
DOI：
10.4161/epi.5.8.13014
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发表时间：
2010-11-01
期刊：
影响因子：
3.7
通讯作者：
Nephew, Kenneth P.
中科院分区：
文献类型：
--
作者：
Bapat, Sharmila A.;Jin, Victor;Nephew, Kenneth P.
“表观遗传可塑性”是指哺乳动物细胞通过染色质重塑相关的基因表达改变来改变其分化状态的能力。虽然表观遗传可塑性与胚胎干细胞的谱系定型密切相关，但最近的研究表明，即使在终末分化的正常细胞、晚期黑色素瘤和乳腺癌细胞中，染色质重塑也会对其微环境的变化做出环境依赖性反应。在当前的研究中，我们通过使用综合方法将细胞表型与染色质修饰（“ChIP 芯片”）以及 mRNA 和 microRNA 表达相关联，将表观遗传可塑性的这种属性扩展到侵袭性卵巢癌细胞。虽然我们鉴定了许多具有众所周知的“二价标记”H3K27me3/H3K4me2 的基因启动子，但我们还报告了铂抗性 CP70 卵巢癌细胞中 14 种不同的、鲜为人知的激活和抑制染色质修饰的二价、三价和四价组合。研究的所有组蛋白标记中的绝大多数（>90%）都位于转录起始位点 2,000 bp 以内的区域，支持在基因调控中的作用。通过对微环境进行简单的改变，即从二维培养物转变为三维培养物，观察到仅抑制性标记的启动子增加（17-38%），同时多价（即并列的许可性和抑制性组蛋白标记）启动子减少（31-21%）。与胚胎/组织干细胞和其他（非卵巢）癌细胞一样，卵巢癌细胞表观遗传可塑性反映了表型中环境响应性改变的固有转录灵活性。这种可塑性有可能被用于治疗这种致命的妇科恶性肿瘤。
"Epigenetic plasticity" refers to the capability of mammalian cells to alter their differentiation status via chromatin remodeling-associated alterations in gene expression. While epigenetic plasticity has been best associated with lineage commitment of embryonic stem cells, recent studies have demonstrated chromatin remodeling even in terminally differentiated normal cells and advanced-stage melanoma and breast cancer cells, in context-dependent responses to alterations in their microenvironment. In the current study, we extend this attribute of epigenetic plasticity to aggressive ovarian cancer cells, by using an integrative approach to associate cellular phenotypes with chromatin modifications ("ChIP-chip") and mRNA and microRNA expression. While we identified numerous gene promoters possessing the well-known "bivalent mark" of H3K27me3/H3K4me2, we also report 14 distinct, lesser known bi-, tri- and tetravalent combinations of activating and repressive chromatin modifications, in platinum-resistant CP70 ovarian cancer cells. The vast majority (>90%) of all the histone marks studied localized to regions within 2,000 bp of transcription start sites, supporting a role in gene regulation. Upon a simple alteration in the microenvironment, transition from two-to three-dimensional culture, an increase (17-38%) in repressive-only marked promoters was observed, concomitant with a decrease (31-21%) in multivalent (i.e., juxtaposed permissive and repressive histone marked) promoters. Like embryonic/tissue stem and other (non-ovarian) carcinoma cells, ovarian cancer cell epigenetic plasticity reflects an inherent transcriptional flexibility for context-responsive alterations in phenotype. It is possible that this plasticity could be therapeutically exploited for the management of this lethal gynecologic malignancy.