Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms.
Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms.
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DOI：
10.3389/fgene.2016.00083
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发表时间：
2016
影响因子：
3.7
通讯作者：
Tollefsbol TO
中科院分区：
文献类型：
--
作者：
Lewis KA;Tollefsbol TO
染色体缩短是正常细胞的特征，被称为末端复制问题。端粒酶是负责在从头合成中延长染色体末端的酶，并且发生在生殖细胞以及大多数恶性肿瘤中。端粒酶有三个亚基：人端粒酶RNA（hTERC）、人端粒酶相关蛋白（hTEP 1）或dyskerin和人端粒酶逆转录酶（hTERT）。hTERC和hTEP 1是组成型表达的，因此端粒酶的酶活性依赖于hTERT的转录。DNA甲基化、组蛋白甲基化和组蛋白乙酰化是参与hTERT表达的基本表观遗传调控。非编码RNA也可以作为hTERT的表观遗传控制的一种形式。这种基于表观遗传的hTERT调节在提供各种生物状态下hTERT控制的可逆性机制方面是重要的。这些包括胚胎hTERT的下调导致衰老和hTERT的上调在超过90%的癌症中发挥关键作用。正常的人类体细胞在hTERT启动子区域内具有非甲基化/低甲基化的CpG岛，而端粒酶阳性细胞矛盾地具有至少部分甲基化的启动子区域，这与DNA甲基化的正常作用相反。启动子区域内H3 K9的组蛋白乙酰化与开放染色质状态相关，使得转录机器具有形成的空间。然而，hTERT的组蛋白甲基化对该基因有不同的控制。启动子区域内H3 K9的单甲基化和二甲基化指示沉默常染色质，而三甲基化H3 K9增强基因转录。非编码RNA可以靶向表观遗传修饰酶以及参与hTERT控制的转录因子。一种可以影响癌细胞表观基因组的表观遗传学饮食是最近受到广泛关注的一个魅力。通过将这种饮食的部分与表观基因组改变治疗相结合，有可能选择性地调节hTERT及其表达的表观遗传控制。
Chromosome-shortening is characteristic of normal cells, and is known as the end replication problem. Telomerase is the enzyme responsible for extending the ends of the chromosomes in de novo synthesis, and occurs in germ cells as well as most malignant cancers. There are three subunits of telomerase: human telomerase RNA (hTERC), human telomerase associated protein (hTEP1), or dyskerin, and human telomerase reverse transcriptase (hTERT). hTERC and hTEP1 are constitutively expressed, so the enzymatic activity of telomerase is dependent on the transcription of hTERT. DNA methylation, histone methylation, and histone acetylation are basic epigenetic regulations involved in the expression of hTERT. Non-coding RNA can also serve as a form of epigenetic control of hTERT. This epigenetic-based regulation of hTERT is important in providing a mechanism for reversibility of hTERT control in various biological states. These include embryonic down-regulation of hTERT contributing to aging and the upregulation of hTERT playing a critical role in over 90% of cancers. Normal human somatic cells have a non-methylated/hypomethylated CpG island within the hTERT promoter region, while telomerase-positive cells paradoxically have at least a partially methylated promoter region that is opposite to the normal roles of DNA methylation. Histone acetylation of H3K9 within the promoter region is associated with an open chromatin state such that transcription machinery has the space to form. Histone methylation of hTERT has varied control of the gene, however. Mono- and dimethylation of H3K9 within the promoter region indicate silent euchromatin, while a trimethylated H3K9 enhances gene transcription. Non-coding RNAs can target epigenetic-modifying enzymes, as well as transcription factors involved in the control of hTERT. An epigenetics diet that can affect the epigenome of cancer cells is a recent fascination that has received much attention. By combining portions of this diet with epigenome-altering treatments, it is possible to selectively regulate the epigenetic control of hTERT and its expression.