Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms
Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms
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DOI：
10.1186/1742-4690-2-64
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发表时间：
2005-10-22
期刊：
影响因子：
3.3
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Taniguchi, Y;Nosaka, K;Matsuoka, M
背景：人类T细胞白血病病毒I型（HTLV-I）经过长时间潜伏后可引起成人T细胞白血病（ATL）。在HTLV-I编码的辅助基因中，Tax基因被认为在肿瘤发生中起核心作用。然而，Tax的表达被几种机制破坏，包括Tax基因的遗传变化、5 '-LTR的缺失/超甲基化。结果：HTLV-I前病毒gag、pol和env基因甲基化程度高于pX区，而5 '-LTR甲基化程度不一，3'-LTR无甲基化。在ATL细胞系中，5 '-LTR的完全DNA甲基化与病毒基因的转录沉默相关。HTLV-I前病毒在原代ATL细胞中的甲基化程度高于携带者，表明其与疾病进展有关。在血清转化者中，血清转化后，在前病毒的内部序列中已经观察到DNA甲基化。综上所述，推测DNA甲基化首先发生在gag、pol和env区，然后在体内沿5'和3'方向延伸，并且当5 '-LTR变得甲基化时，病毒转录沉默。对HTLV-Ⅰ前病毒组蛋白修饰的分析表明，甲基化前病毒与低乙酰化有关。然而，在新鲜的ATL细胞中不能检测到tax基因转录本，无论在5 '-LTR中的组蛋白H3是否被过度乙酰化。结论：前病毒的表观遗传学改变通过抑制病毒基因的转录，促进ATL细胞逃避宿主免疫系统。此外，这项研究表明，存在另一种可逆的机制，抑制税收基因的转录没有DNA甲基化和hypoacetylated组蛋白。
Background: Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. Among accessory genes encoded by HTLV-I, the tax gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the tax gene, deletion/hypermethylation of 5'-LTR. To clarify the role of epigenetic changes, we analyzed DNA methylation and histone modification in the whole HTLV-I provirus genome.Results: The gag, pol and env genes of HTLV-I provirus were more methylated than pX region, whereas methylation of 5'-LTR was variable and 3'-LTR was not methylated at all. In ATL cell lines, complete DNA methylation of 5'-LTR was associated with transcriptional silencing of viral genes. HTLV-I provirus was more methylated in primary ATL cells than in carrier state, indicating the association with disease progression. In seroconvertors, DNA methylation was already observed in internal sequences of provirus just after seroconversion. Taken together, it is speculated that DNA methylation first occurs in the gag, pol and env regions and then extends in the 5' and 3' directions in vivo, and when 5'-LTR becomes methylated, viral transcription is silenced. Analysis of histone modification in the HTLV-I provirus showed that the methylated provirus was associated with hypoacetylation. However, the tax gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after in vitro culture in such ATL cells.Conclusion: These results showed that epigenetic changes of provirus facilitated ATL cells to evade host immune system by suppressing viral gene transcription. In addition, this study shows the presence of another reversible mechanism that suppresses the tax gene transcription without DNA methylation and hypoacetylated histone.