Jin Seung-Gi, Xiong Wenying, Wu Xiwei, Yang Lu, Pfeifer Gerd P
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Genomics. 2015 Dec;106(6):322-30. doi: 10.1016/j.ygeno.2015.09.004. Epub 2015 Sep 15.
Using MIRA-seq, we have characterized the DNA methylome of metastatic melanoma and normal melanocytes. Individual tumors contained several thousand hypermethylated regions. We discovered 179 tumor-specific methylation peaks present in all (27/27) melanomas that may be effective disease biomarkers, and 3113 methylation peaks were seen in >40% of the tumors. We found that 150 of the approximately 1200 tumor-associated methylation peaks near transcription start sites (TSSs) were marked by H3K27me3 in melanocytes. DNA methylation in melanoma was specific for distinct H3K27me3 peaks rather than for broadly covered regions. However, numerous H3K27me3 peak-associated TSS regions remained devoid of DNA methylation in tumors. There was no relationship between BRAF mutations and the number of methylation peaks. Gene expression analysis showed upregulated immune response genes in melanomas presumably as a result of lymphocyte infiltration. Down-regulated genes were enriched for melanocyte differentiation factors; e.g., KIT, PAX3 and SOX10 became methylated and downregulated in melanoma.
利用MIRA-seq技术，我们对转移性黑色素瘤和正常黑素细胞的DNA甲基化组进行了特征分析。单个肿瘤包含数千个高甲基化区域。我们发现，在所有（27/27）黑色素瘤中均存在179个肿瘤特异性甲基化峰，这些峰可能是有效的疾病生物标志物，并且在超过40%的肿瘤中观察到3113个甲基化峰。我们发现，黑素细胞中转录起始位点（TSS）附近约1200个肿瘤相关甲基化峰中的150个被H3K27me3标记。黑色素瘤中的DNA甲基化对不同的H3K27me3峰具有特异性，而非广泛覆盖的区域。然而，许多与H3K27me3峰相关的TSS区域在肿瘤中仍未发生DNA甲基化。BRAF突变与甲基化峰的数量之间没有关系。基因表达分析显示，黑色素瘤中免疫反应基因上调，推测这是淋巴细胞浸润的结果。下调的基因富含黑素细胞分化因子；例如，KIT、PAX3和SOX10在黑色素瘤中发生甲基化并下调。
