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首页> 外文期刊>Oncogene >Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells
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Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells

机译：差异表达的基因由组蛋白3赖氨酸9的人癌细胞中的三甲基化标记

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Histone H3 lysine 9 trimethylation (H3K9Me3) has been associated with transcriptional repression, but recent findings implicate this chromatin modification in transcriptional activation and mRNA elongation by RNA polymerase II. Here, we applied immunoprecipitation (IP) with a custom DNA tiling microarray containing many transcription factors important in development and cancer (for example homeotic genes; N=683 total genes) to explore the relationship between H3K9Me3 and other histone modifications with the differential expression of genes. Cancer cell lines derived from different tissues (2 leukemia, 2 medulloblastoma) were characterized with IP antibodies to H3K9Me3, H3K4 dimethylation (H3K4Me2) and H3K9 acetylation (H3K9Ac). MV4-11 is known to overexpress the HOXA9 and MEIS1 genes, whereas D283 overexpresses the OTX2 homeobox gene. Gene expression was assessed by Affymetrix U133 array. Mapping the number and size of histone markings demonstrated significant colocalization of H3K9Ac and H3K4Me2 with H3K9Me3, indicating a pattern of putative ‘activating’ and ‘repressive’ markings. The median site size was 600–821?bp and 72–95% or 53–80% of chromatin signal sites were located within 1?kb or 500?bp of transcription start sites (TSS), respectively. A relatively small number of genes displayed additional H3K9Me3 sites in the 5′-region distant from the TSS. Comparing genes with modification sites to those without sites in their promoters confirmed the positive associations of H3K9Ac and H3K4Me2 with gene expression and revealed that H3K9Me3 is associated with active genes rather than being a repressive marking as previously thought. The positive regulatory effect of all three types of modifications were quantitatively correlated with site size, and applied to absolute gene expression within a single cell line as well as relative expression among pairs of cell lines. Extended patterns of H3K9Me3 upstream of some genes (for example HOXA9 and OTX2) may result from the action of multiple promoter elements. We found an inverse relationship between promoter DNA hypermethylation and H3K9Me3 in three studied genes (HOXA9, TMS1, RASSF1A). The localization of H3K9Me3 downstream of the TSSs of expressed genes and not within promoter regions of hypermethylated and silenced genes is consistent with the proposed coupling of H3K9Me3 with RNA polymerase II. Our results indicate a need for revising aspects of the histone code involving H3 lysine methylation. Awareness of H3K9Me3 as a mark of gene activity, not repression, is especially important for the classification of human cancer using chromatin and histone profiles.
机译：组蛋白H3赖氨酸9对三甲基化（H3K9ME3）与转录抑制有关，但最近的发现暗示了通过RNA聚合酶II的转录激活和mRNA伸长的该染色质改性。在这里，我们用含有许多在发育和癌症中重要的转录因子（例如归属基因; n = 683总基因），应用免疫沉淀（IP）用含有许多重要的转录因子，以探讨H3K9ME3与其他组蛋白修饰之间的关系基因。衍生自不同组织（2只白血病，2个Medulloblastoma）的癌细胞系具有IP抗体至H3K9ME3，H3K4二甲基化（H3K4ME2）和H3K9乙酰化（H3K9Ac）的IP抗体。已知MV4-11过筛Hoxa9和Meis1基因，而D283过表达OTX2 Homeobox基因。通过Affymetrix U133阵列评估基因表达。映射组蛋白标记的数量和尺寸显示H3K9AC和H3K4ME2的显着分致化，H3K9ME3表示推定的“激活”和“压抑”标记的模式。中位数位数为600-821？BP和72-95 ％或53-80 ％的染色质信号位点分别位于1？Kb或500μl的转录开始点（TSS）内。相对少量的基因在来自TSS的5'区域中显示出额外的H3K9ME3位点。将具有改性位点的基因与其启动子的没有位点进行比较，证实了H3K9AC和H3K4ME2与基因表达的阳性关联，并揭示了H3K9ME3与活性基因相关，而不是如前所述的抑制标记。所有三种改性的阳性调节效果与位点大小定量相关，并施加到单细胞系中的绝对基因表达以及对细胞系成对的相对表达。一些基因的上游H3K9ME3的扩展模式（例如Hoxa9和OTX2）可能是由多个启动子元素的作用产生的。我们发现了启动子DNA高甲基化和H3K9ME3在三个研究的基因（HOXA9，TMS1，RASSF1a）中的反比关系。表达基因TSS下游H3K9ME3的定位与高甲基化和沉默基因的启动子区域内的局部化与H3K9ME3与RNA聚合酶II的提出偶联一致。我们的结果表明需要修改涉及H3赖氨酸甲基化的组蛋白代码的方面。对H3K9ME3的认识作为基因活性的标志，而不是抑制，对于使用染色质和组蛋白谱进行人类癌的分类尤为重要。

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