Allele-specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (TERT) associates with TERT expression in multiple cancers.
Allele-specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (TERT) associates with TERT expression in multiple cancers.
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DOI：
10.1002/1878-0261.12786
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发表时间：
2020-10
影响因子：
6.6
通讯作者：
Cech TR
中科院分区：
文献类型：
--
作者：
Rowland TJ;Bonham AJ;Cech TR
在癌症中，TERT基因的活跃表达与高甲基化的CpG岛矛盾地相关。在这里，我们表明，在833癌细胞系代表23种组织类型，近端启动子包含保守的低甲基化。在具有单等位基因TERT表达的品系中，近端启动子甲基化降低与活性等位基因相关。因此，近端TERT启动子具有典型的DNA甲基化。 端粒酶逆转录酶（TERT）在绝大多数人类癌症中病理性表达，但其表达的表观遗传调控才刚刚开始被理解。特别是，癌细胞中的活性TERT基因已被表征为具有高甲基化的CpG岛，与DNA甲基化与基因抑制的一般关联相反。在这里，我们分析了23种不同组织类型的833种人类癌细胞系中的TERT启动子CpG甲基化，发现了CpG岛上游部分的高甲基化和包括近端TERT启动子和外显子1在内的区域的更保守的低甲基化。在具有单等位基因表达的TERT的细胞系中，我们发现了近端TERT启动子的等位基因甲基化。这包括具有-124或-146激活启动子突变的细胞系以及野生型TERT癌细胞系。在这些细胞系类型中，近端启动子甲基化降低与活性等位基因相关。与具有单等位基因表达的TERT的细胞相比，具有双等位基因表达的TERT的细胞系在近端TERT启动子中具有甚至更低的甲基化。因此，在来自许多不同组织的癌症的细胞系中，TERT近端启动子具有典型的DNA甲基化，其中低甲基化与增加的TERT表达相关。
In cancer, active expression of the TERT gene paradoxically correlates with a hypermethylated CpG island. Here, we show that in 833 cancer cell lines representing 23 tissue types, the proximal promoter contains conserved hypomethylation. In lines with monoallelic TERT expression, decreased proximal promoter methylation associates with the active allele. Thus, the proximal TERT promoter has canonical DNA methylation. Telomerase reverse transcriptase (TERT) is pathologically expressed in the vast majority of human cancers, but the epigenetic regulation of its expression is only beginning to be understood. In particular, the active TERT gene in cancer cells has been characterized as having a hypermethylated CpG island, opposite to the general association of DNA methylation with gene repression. Here, we analyzed TERT promoter CpG methylation in 833 human cancer cell lines representing 23 different tissue types and found hypermethylation of the upstream portion of the CpG island and more conserved hypomethylation of a region including the proximal TERT promoter and exon 1. In cell lines with monoallelic expression of TERT, we found allelic methylation of the proximal TERT promoter. This included cell lines with the −124 or −146 activating promoter mutation as well as wild‐type TERT cancer lines. In these cell line types, decreased proximal promoter methylation is associated with the active allele. Compared to cells with monoallelic expression of TERT, lines with biallelic expression of TERT had even lower methylation in the proximal TERT promoter. Thus, in cell lines from cancers of many different tissues, the TERT proximal promoter has canonical DNA methylation, with low methylation correlating with increased TERT expression.
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影响因子：
6.2
作者：
Huang, F. W.;Bielski, C. M.;Kryukov, G. V.
通讯作者：
Kryukov, G. V.
影响因子：
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作者：
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通讯作者：
Tollefsbol, TO
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作者：
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通讯作者：
Sellers, William R.
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作者：
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通讯作者：
Zeiger, Martha A.
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作者：
Cheung, Hoi-Hung;Lee, Tin-Lap;Rennert, Owen M.;Chan, Wai-Yee
通讯作者：
Chan, Wai-Yee