Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes
Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes
复制标题
DOI：
10.1038/leu.2012.253
复制
发表时间：
2013-03-01
期刊：
影响因子：
11.4
通讯作者：
Hernandez-Rivas, J. M.
中科院分区：
文献类型：
--
作者：
del Rey, M.;O'Hagan, K.;Hernandez-Rivas, J. M.
基因表达谱特征可用于对骨髓增生异常综合征（MDS）患者的亚型进行分类。然而，关于MDS的整体甲基化状态的报道很少。全基因组表观遗传调控标记与基因表达水平的整合将提供关于MDS和健康对照之间生物学差异的额外信息。使用高密度微阵列测量基因表达和甲基化状态。共有552个差异甲基化的CpG位点被确定为存在于低风险MDS中;高甲基化基因比低甲基化基因更常见。此外，mRNA表达谱确定了1005个基因，这些基因在低风险MDS和对照组之间存在显著差异。表观遗传和表达谱的综合分析显示，66.7%的高甲基化基因在低风险MDS病例中表达不足。基因网络分析揭示了与低危MDS组相关的分子机制，包括改变的细胞凋亡途径。两个关键的凋亡基因BCL 2和ETS 1被鉴定为沉默基因。此外，IL 27 RA和DICER 1的高甲基化和低表达影响免疫应答和microRNA生物合成。我们的综合分析表明，异常表观遗传调控是低风险MDS患者的标志，并可能在这些疾病中发挥核心作用。白血病（2013）27，610-618; doi：10.1038/leu.2012.253
Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. Leukemia (2013) 27, 610-618; doi:10.1038/leu.2012.253