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首页> 外文期刊>Molecular and Cellular Biology >Progressive increases in the methylation status and heterochromatinization of the myoD CpG island during oncogenic transformation.
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Progressive increases in the methylation status and heterochromatinization of the myoD CpG island during oncogenic transformation.

机译：在致癌转化过程中，myoD CpG岛的甲基化状态和异染色质逐渐增加。

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Alterations in DNA methylation patterns are one of the earliest and most common events in tumorigenesis. Overall levels of genomic methylation often decrease during transformation, but localized regions of increased methylation have been observed in the same tumors. We have examined changes in the methylation status of the muscle determination gene myoD, which contains a CpG island, as a function of oncogenic transformation. This CpG island underwent de novo methylation during immortalization of 10T1/2 cells, and progressively more sites became methylated during the subsequent transformation of the cells to oncogenicity. The greatest increase in methylation occurred in the middle of the CpG island in exon 1 during transformation. Interestingly, no methylation was apparent in the putative promoter of myoD in either the 10T1/2 cell line or its transformed derivative. The large number of sites in the CpG island that became methylated during transformation was correlated with heterochromatinization of myoD as evidenced by a decreased sensitivity to cleavage of DNA in nuclei by MspI. A site in the putative promoter also became insensitive to MspI digestion in nuclei, suggesting that the chromatin structural changes extended beyond the areas of de novo methylation. Unlike Lyonized genes on the inactive X chromosome, whose timing of replication is shifted to late S phase, myoD replicated early in S phase in the transformed cell line. Methylation analysis of myoD in DNAs from several human tumors, which presumably do not express the gene, showed that hypermethylation also frequently occurs during carcinogenesis in vivo. Thus, the progressive increase in methylation of myoD during immortalization and transformation coinciding with a change in chromatin structure, as illustrated by the in vitro tumorigenic model, may represent a common mechanism in carcinogenesis for permanently silencing the expression of genes which can influence cell growth and differentiation.
机译：DNA甲基化模式的改变是肿瘤发生中最早，最常见的事件之一。基因组甲基化的总体水平通常在转化过程中降低，但是在同一肿瘤中观察到甲基化增加的局部区域。我们已经检查了肌肉测定基因myoD的甲基化状态的变化，其中该基因包含CpG岛，这是致癌转化的函数。这个CpG岛在10T1 / 2细胞永生化过程中经历了从头甲基化，在随后的细胞转化为致癌性过程中，越来越多的位点被甲基化。甲基化的最大增加发生在转化过程中外显子1的CpG岛中间。有趣的是，在10T1 / 2细胞系或其转化的衍生物中，myoD的推定启动子中没有明显的甲基化。 CpG岛中大量在转化过程中甲基化的位点与myoD的异染色质化相关，MspI对核中DNA裂解的敏感性降低证明了这一点。推定的启动子中的一个位点也变得对核中的MspI消化不敏感，这表明染色质的结构变化超出了从头甲基化的范围。与非活性X染色体上的Lyonized基因不同，后者复制的时间转移到了S期晚期，而myoD在转化细胞系的S期早期复制了。可能不表达该基因的几种人类肿瘤的DNA中myoD的甲基化分析表明，高甲基化在体内致癌过程中也经常发生。因此，如体外致瘤模型所示，在永生化和转化过程中，myoD甲基化的逐步增加与染色质结构的变化相吻合，可能代表了致癌作用中的一种共同机制，该机制可永久沉默可影响细胞生长和生长的基因的表达。差异化。

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