The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer.
|核心内容：
DNA CpG甲基化过程已被广泛研究了50多年，并揭示了CpG岛甲基化状态的改变与基因表达之间的关系。
因此，DNA CpG甲基化参与了发育和动态平衡过程中基因表达的控制，同时也是癌症的驱动机制。
全基因组技术和复杂的统计分析方法的发展开创了一个广泛分析的时代，例如在癌症领域，对改变的DNA CpG甲基化、基因表达和肿瘤状态之间的关系进行了广泛的分析。
例如，通过癌症基因组图谱(TCGA)的研究人员，这类基因组数据量的显著增加使得人们能够剖析DNA CpG甲基化密度和分布、基因表达和肿瘤预后之间的关系。
通过这种方式，现在可以测试DNA CpG甲基化变化和基因表达之间的全基因组相关性。
图1 DNA 甲基化途径基因的表达及其与肿瘤预后的关系。
(a)热图显示癌症基因组图谱(TCGA)前列腺癌(PRAD)队列(n = 497)中 DNA 甲基化途径的常见且显著改变的 mRNA 表达。在至少80% 的肿瘤中检测到的所有基因的基因表达量作为正常组织的相对 z 值。聚类成员显著识别侵袭性肿瘤(p < 0.006) ;
(b)负相关性和正相关性(Pearson 相关性 <-0.6或 > 0.6)为这些常见改变的 DNA 甲基化通路(n = 21)和所有其他可检测的基因 TCGA 队列(n = 16,785)中的每个基因(n = 16,785)被测量和165个来自 Lynch 等人综述的 DNA 共同目标的富集。
（c）热图显示了与吲哚乙胺 n- 甲基转移酶(INMT)和甲硫氨酸腺苷转移酶2 b (MAT2B)有显著相关性的基因表达的共同和显著改变，这些基因是 TCGA PRAD 队列中已知的 DNA 甲基化靶点。集群成员显著识别侵袭性肿瘤(p < 0.0007)。
或许令人惊讶的是，这些关联只有数百个，而不是数千个基因中被检测到，而且关联的方向既有积极的，也有消极的。
这或许表明，癌症系统中的CpG甲基化事件可以作为疾病的驱动力，但其影响可能比人们想象的更有限。
此外，正相关和负相关暗示着直接和间接的事件和不完全的理解。
在前列腺癌TCGA队列中，我们研究了控制DNA甲基化的基因、已知的DNA甲基化靶标和肿瘤状态之间的关系。
这揭示了控制腺苷-l-蛋氨酸(SAM)合成的基因与侵袭性肿瘤亚群中DNA甲基化靶标表达的改变有关。原文摘要：
The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of -adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors.
参考文献：https://sci-hub.se/10.3390/biom7010015
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