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Hypoxia increases genome-wide bivalent epigenetic marking by specific gain of H3K27me3

机译：低氧通过H3K27me3的特定增益增加全基因组二价表观遗传标记

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Background Trimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity during development and differentiation. Whether H3K4me3 and H3K27me3 changes dynamically in response to altered microenvironmental conditions, including low-oxygen conditions commonly present in solid tumors, is relatively unknown. Demethylation of H3K4me3 and H3K27me3 is mediated by oxygen and 2-oxoglutarate dioxygenases enzymes, suggesting that oxygen deprivation (hypoxia) may influence histone trimethylation. Using the MCF7 breast epithelial adenocarcinoma cell model, we have determined the relationship between epigenomic and transcriptomic reprogramming as a function of fluctuating oxygen tension. Results We find that in MCF7, H3K4me3 and H3K27me3 marks rapidly increase at specific locations throughout the genome and are largely reversed upon reoxygenation. Whereas dynamic changes are relatively highest for H3K27me3 marking under hypoxic conditions, H3K4me3 occupation is identified as the defining epigenetic marker of transcriptional control. In agreement with the global increase of H3K27 trimethylation, we provide direct evidence that the histone H3K27me3 demethylase KDM6B/JMJD3 is inactivated by limited oxygen. In situ immunohistochemical analysis confirms a marked rise of histone trimethylation in hypoxic tumor areas. Acquisition of H3K27me3 at H3K4me3-marked loci results in a striking increase in “bivalent” epigenetic marking. Hypoxia-induced bivalency substantially overlaps with embryonal stem cell-associated genic bivalency and is retained at numerous loci upon reoxygenation. Transcriptional activity is selectively and progressively dampened at bivalently marked loci upon repeated exposure to hypoxia, indicating that this subset of genes uniquely maintains the potential for epigenetic regulation by KDM activity. Conclusions These data suggest that dynamic regulation of the epigenetic state within the tumor environment may have important consequences for tumor plasticity and biology.
机译：背景在组蛋白H3赖氨酸4（H3K4me3）和赖氨酸27（H3K27me3）处的三甲基化控制发育和分化过程中的基因活性。相对未知，H3K4me3和H3K27me3是否响应改变的微环境条件（包括实体瘤中常见的低氧条件）而动态变化。 H3K4me3和H3K27me3的去甲基化是由氧气和2-氧戊二酸双加氧酶介导的，这表明缺氧（缺氧）可能会影响组蛋白三甲基化。使用MCF7乳腺上皮腺癌细胞模型，我们确定了表观基因组和转录组重编程之间的关系是氧张力的波动。结果我们发现，在MCF7中，H3K4me3和H3K27me3标志在整个基因组的特定位置迅速增加，并且在复氧后大部分被逆转。在缺氧条件下，H3K27me3标记的动态变化相对最高，而H3K4me3的占领被确定为转录控制的定义性表观遗传标记。与H3K27三甲基化的全球增加相一致，我们提供直接证据表明组蛋白H3K27me3脱甲基酶KDM6B / JMJD3被有限的氧气灭活。原位免疫组化分析证实低氧肿瘤区域中组蛋白三甲基化的显着升高。在H3K4me3标记的基因座处获取H3K27me3导致“二价”表观遗传标记显着增加。缺氧诱导的双价与胚胎干细胞相关的基因双价基本重叠，并且在复氧后保留在许多基因座上。重复暴露于缺氧状态下，转录活性在二价标记的基因座上被选择性和逐步抑制，表明该基因子集独特地保持了通过KDM活性进行表观遗传调控的潜力。结论这些数据表明，肿瘤环境中表观遗传状态的动态调节可能对肿瘤可塑性和生物学产生重要影响。

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