Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors
Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors
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DOI：
10.1002/ijc.27429
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发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Kretzschmar, Hans A.
中科院分区：
文献类型：
--
作者：
Kraus, Theo F. J.;Globisch, Daniel;Kretzschmar, Hans A.
基因组 DNA 中的 5-甲基胞嘧啶 (5mC) 在胚胎发育和肿瘤生物学中具有重要的表观遗传功能。 5-羟甲基胞嘧啶 (5hmC) 通过 TET（十一个十一易位）酶的作用从 5mC 生成，可能是 5mC 进一步氧化并最终去甲基化的中间体。我们使用免疫组织化学 (IHC) 和同位素液相色谱质谱 (LC-MS) 来研究 5hmC 在人脑和脑肿瘤中的存在和分布。在正常成人大脑中，IHC 在皮质中发现了 61.5% 的 5hmC 阳性细胞，在白质 (WM) 区域中发现了 32.4% 的 5hmC 阳性细胞。在肿瘤中，细胞阳性染色范围从胶质母细胞瘤 (GBM)（WHO IV 级）的 1.1% 到 I 级胶质瘤（毛细胞星形细胞瘤）的 8.9%。在正常成人大脑中，LC-MS 在皮质区域也显示出最高值（1.17% 5hmC/dG [脱氧鸟苷]），在大脑 WM 中，我们测得约为 0.70% 5hmC/dG。 5hmC 水平与肿瘤分化相关，范围从 GBM（WHO IV 级）中的最低值 0.078% 5hmC/dG 到 WHO II 级弥漫性星形细胞瘤中的 0.24% 5hmC/dG。 5hmC 测量值与 5mC 值无关。我们发现基因组中5hmC阳性细胞的数量和5hmC/dG的量被认为与胚胎干细胞的多能性和谱系定型相关，也与脑肿瘤分化和退行性变有关。
5-Methylcytosine (5mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5hmC) is generated from 5mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5hmC positive cells in the cortex and 32.4% 5hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5hmC/dG. 5hmC levels were related to tumor differentiation, ranging from lowest values of 0.078% 5hmC/dG in GBMs (WHO Grade IV) to 0.24% 5hmC/dG in WHO Grade II diffuse astrocytomas. 5hmC measurements were unrelated to 5mC values. We find that the number of 5hmC positive cells and the amount of 5hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia.