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Genome-wide characterization of 5-hydoxymethylcytosine in melanoma reveals major differences with nevus.
黑色素瘤中 5-羟甲基胞嘧啶的全基因组表征揭示了与痣的主要差异。
- 影响因子:3.04
- DOI:10.1002/gcc.22837
- 作者列表:"Salgado C","Oosting J","Janssen B","Kumar R","Gruis N","van Doorn R
- 发表时间:2020-02-03
Abstract
:Melanoma demonstrates altered patterns of DNA methylation that are associated with genetic instability and transcriptional repression of numerous genes. Active DNA demethylation is mediated by TET enzymes that catalyze conversion of 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC). Loss of hmC occurs in melanoma and correlates with disease progression. Here we analyzed the genomic distribution of hmC along with mC in nevus and melanoma using oxidative bisulfite chemistry combined with high-density arrays. HmC was enriched relative to mC at enhancers, 5'UTR regions and CpG shores in nevus and melanoma samples, pointing to specific TET enzyme activity. The proportion of interrogated CpG sites with high hmC levels was lower in melanoma (0.54%) than in nevus (2.0%). Depletion of hmC in melanoma was evident across all chromosomes and intragenic regions, being more pronounced in metastatic than in non-metastatic tumors. The patterns of hmC distribution in melanoma samples differed significantly from those in nevus samples, exceeding differences in mC patterns. We identified specific CpG sites and regions with significantly lower hmC levels in melanoma than in nevus that might serve as diagnostic markers. Differentially hydroxymethylated regions localized to cancer-related genes, including the PTEN gene promoter, suggesting that deregulated DNA hydroxymethylation may contribute to melanoma pathogenesis.
摘要
: 黑色素瘤显示 DNA 甲基化模式改变,与遗传不稳定性和众多基因的转录抑制相关。活性 DNA 去甲基化是由催化 5-甲基胞嘧啶 (mC) 转化为 5-羟甲基胞嘧啶 (hmC) 的 TET 酶介导的。HmC 的丢失发生在黑色素瘤中,并与疾病进展相关。这里我们使用氧化亚硫酸氢盐化学结合高密度阵列分析了 hmC 与 mC 在痣和黑色素瘤中的基因组分布。HmC 相对于 mC 在色素痣和黑色素瘤样本中的增强子、 5 'utr 区域和 CpG 海岸富集,指向特定的 TET 酶活性。被询问的 CpG 位点具有高 hmC 水平的比例在黑色素瘤中 (0.54%) 低于痣 (2.0%)。黑色素瘤中 hmC 的耗竭在所有染色体和基因内区域都很明显,在转移性肿瘤中比在非转移性肿瘤中更明显。HmC 在黑色素瘤样本中的分布模式与痣样本中的分布模式显著不同,超过了 mC 模式的差异。我们确定了黑色素瘤中 hmC 水平显著低于痣的特定 CpG 位点和区域,可能作为诊断标志物。差异羟甲基化区域定位于癌症相关基因,包括 PTEN 基因启动子,提示失调的 DNA 羟甲基化可能有助于黑色素瘤发病机制。
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