Chromosome-specific retention of cancer-associated DNA hypermethylation following pharmacological inhibition of DNMT1.
Chromosome-specific retention of cancer-associated DNA hypermethylation following pharmacological inhibition of DNMT1.
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DOI：
10.1038/s42003-022-03509-3
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发表时间：
2022-06-02
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
由于计算困难，癌细胞中X染色体的DNA甲基化状态经常被忽视。X染色体上的大多数CpG岛在正常雌性细胞中是单等位基因甲基化的，并且在雄性细胞中仅以单拷贝存在。我们在几个月内用增加剂量的DNA甲基转移酶1（DNMT 1）特异性抑制剂（GSK 3685032/GSK 5032）处理了来自男性（HCT 116）和女性（RKO）的两种结直肠癌细胞系，以尽可能多地去除非必需的CpG甲基化。对剩余DNA甲基化组的分析揭示了X染色体上DNA甲基化的意想不到的富集保留。引人注目的是，所鉴定的保留X染色体DNA甲基化模式准确地预测了TCGA COAD/READ队列中结肠癌患者甲基化组中的从头DNA超甲基化。这些结果表明，重新检查肿瘤的X连锁DNA甲基化变化可能使我们更好地理解癌症相关基因的表观遗传沉默的重要性。显示了在药物抑制DNMT 1后癌症相关DNA超甲基化的染色体特异性保留，与常染色体相比，X染色体上存在残留的CpG甲基化，表明甲基化的单独机制。
The DNA methylation status of the X-chromosome in cancer cells is often overlooked because of computational difficulties. Most of the CpG islands on the X-chromosome are mono-allelically methylated in normal female cells and only present as a single copy in male cells. We treated two colorectal cancer cell lines from a male (HCT116) and a female (RKO) with increasing doses of a DNA methyltransferase 1 (DNMT1)-specific inhibitor (GSK3685032/GSK5032) over several months to remove as much non-essential CpG methylation as possible. Profiling of the remaining DNA methylome revealed an unexpected, enriched retention of DNA methylation on the X-chromosome. Strikingly, the identified retained X-chromosome DNA methylation patterns accurately predicted de novo DNA hypermethylation in colon cancer patient methylomes in the TCGA COAD/READ cohort. These results suggest that a re-examination of tumors for X-linked DNA methylation changes may enable greater understanding of the importance of epigenetic silencing of cancer related genes. Chromosome specific retention of cancer associated DNA hypermethylation following pharmacological inhibition of DNMT1 is shown, with residual CpG methylation on the X chromosome compared to autosomes, suggesting a separate mechanism of methylation.
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影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
50.3
作者：
Yang X;Han H;De Carvalho DD;Lay FD;Jones PA;Liang G
通讯作者：
Liang G
影响因子：
8
作者：
Zeller, C.;Dai, W.;Brown, R.
通讯作者：
Brown, R.
影响因子：
5.3
作者：
Liang, GG;Chan, MF;Jones, PA
通讯作者：
Jones, PA
DOI：
10.1073/pnas.0604602103
发表时间：
2006-09-19
影响因子：
11.1
作者：
Egger, Gerda;Jeong, Shinwu;Liang, Gangning
通讯作者：
Liang, Gangning