Hypomethylation coordinates antagonistically with hypermethylation in cancer development: a case study of leukemia.
Hypomethylation coordinates antagonistically with hypermethylation in cancer development: a case study of leukemia.
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DOI：
10.1186/s40246-016-0071-5
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发表时间：
2016-07-25
期刊：
影响因子：
4.5
通讯作者：
Xu D
中科院分区：
文献类型：
--
作者：
Kushwaha G;Dozmorov M;Wren JD;Qiu J;Shi H;Xu D
甲基化变化在癌症中很常见，但需要了解高甲基化和低甲基化区域的变化如何协调，与基因组特征相关，并影响基因表达，以更好地了解其生物学意义。高甲基化的功能意义已被充分研究，但低甲基化的功能意义仍然有限。在这里，从患者/对照队列收集配对表达和甲基化样本，我们试图更好地表征发生在B细胞慢性淋巴细胞白血病（B-CLL）样本中的癌症中的基因表达和甲基化变化。在整个数据集中，我们发现，与许多一致性差的低和高度保守的超DMR相比，样品中一致的差异低甲基化区域（C-DMR）相对较少。然而，在hypo-C-DMR中的基因往往与那些在hyper-C-DMR中的功能拮抗相关，如分化，细胞周期调节和增殖，这表明甲基化变化的协调调节。发现B-CLL中的Hypo-C-DMR富含关键信号传导途径，如B细胞受体和p53途径以及B淋巴细胞生成所必需的基因/基序。与高甲基化引起的转录沉默机制相反，低-C-DMR倾向于接近表达升高的基因。Hypo-C-DMR倾向于在激活H4 K4 me 1/2/3、H3 K79 me 2和H3 K27 ac组蛋白修饰的区域富集。相比之下，由EZH 2、SUZ 12、CTCF结合位点、抑制性H3 K27 me 3标记和“抑制/平衡启动子”状态标记的多梳抑制复合物2（PRC 2）签名与超C-DMR相关。在内含子（36%）、3′端非翻译区（29%）和基因间区（24%）发现了大量的低C-DMR。这些基因区域中的许多也与增强子重叠。3′UTR外显子CpG甲基化与基因表达呈弱正相关。相反，5′UTR甲基化与表达呈负相关。为了更好地表征甲基化和表达变化之间的重叠，我们确定了与“凋亡”和“白细胞活化”相关的相关模块。尽管在疾病表现的临床异质性，一些甲基化的变化，无论是低和高，似乎是常见的B-CLL。低甲基化似乎在癌症进展中起着积极的、靶向的和互补的作用，并且在癌症过程中以协调的方式与高甲基化相互作用。本文的在线版本（doi：10.1186/s40246-016-0071-5）包含补充材料，可供授权用户使用。
Methylation changes are frequent in cancers, but understanding how hyper- and hypomethylated region changes coordinate, associate with genomic features, and affect gene expression is needed to better understand their biological significance. The functional significance of hypermethylation is well studied, but that of hypomethylation remains limited. Here, with paired expression and methylation samples gathered from a patient/control cohort, we attempt to better characterize the gene expression and methylation changes that take place in cancer from B cell chronic lymphocyte leukemia (B-CLL) samples. Across the dataset, we found that consistent differentially hypomethylated regions (C-DMRs) across samples were relatively few compared to the many poorly consistent hypo- and highly conserved hyper-DMRs. However, genes in the hypo-C-DMRs tended to be associated with functions antagonistic to those in the hyper-C-DMRs, like differentiation, cell-cycle regulation and proliferation, suggesting coordinated regulation of methylation changes. Hypo-C-DMRs in B-CLL were found enriched in key signaling pathways like B cell receptor and p53 pathways and genes/motifs essential for B lymphopoiesis. Hypo-C-DMRs tended to be proximal to genes with elevated expression in contrast to the transcription silencing-mechanism imposed by hypermethylation. Hypo-C-DMRs tended to be enriched in the regions of activating H4K4me1/2/3, H3K79me2, and H3K27ac histone modifications. In comparison, the polycomb repressive complex 2 (PRC2) signature, marked by EZH2, SUZ12, CTCF binding-sites, repressive H3K27me3 marks, and “repressed/poised promoter” states were associated with hyper-C-DMRs. Most hypo-C-DMRs were found in introns (36 %), 3′ untranslated regions (29 %), and intergenic regions (24 %). Many of these genic regions also overlapped with enhancers. The methylation of CpGs from 3′UTR exons was found to have weak but positive correlation with gene expression. In contrast, methylation in the 5′UTR was negatively correlated with expression. To better characterize the overlap between methylation and expression changes, we identified correlation modules that associate with “apoptosis” and “leukocyte activation”. Despite clinical heterogeneity in disease presentation, a number of methylation changes, both hypo and hyper, appear to be common in B-CLL. Hypomethylation appears to play an active, targeted, and complementary role in cancer progression, and it interplays with hypermethylation in a coordinated fashion in the cancer process. The online version of this article (doi:10.1186/s40246-016-0071-5) contains supplementary material, which is available to authorized users.