Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs).
Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs).
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DOI：
10.3390/v9060130
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发表时间：
2017-05-31
期刊：
影响因子：
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通讯作者：
Magiorkinis G
中科院分区：
文献类型：
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作者：
Hurst TP;Magiorkinis G
转座因子，包括内源性逆转录病毒（ERV），几乎占人类基因组的45%。这可能是一个重大的致病负担，但越来越明显的是，许多这些元素有一个积极的贡献，使正常的人体生理。特别是，人类ERVs（HERVs）对基因调控和非编码RNA表达的贡献已经在新的和新兴的基因组技术的帮助下被揭示出来。HERV具有共同的编码开放阅读框（ORF）的前病毒结构，两侧是两个长末端重复序列（LTR）。然而，在进化过程中，由于宿主防御机制，大多数序列含有INDEL、突变或已通过重组减少为单个LTR。这些INDEL和突变降低HERV活性。然而，对于宿主细胞而言存在权衡，因为HERV可以提供有益的遗传变异来源，但伴随这种益处而来的是致病活性和在基因组内传播的风险。例如，LTR是至关重要的，因为它们含有启动子序列，并且不仅可以调节HERV表达，还可以调节人类基因的表达。即使LTR位于基因间区域或与基因的其余部分处于反义方向，也是如此。如果不受控制，这种启动子活性可能会破坏正常的基因表达或转录物加工（例如，拼接）。因此，控制HERV，特别是其LTR对于细胞管理这些元件是必不可少的，并且这种控制在多个水平上实现，包括允许HERV在种系中表达但在大多数体细胞组织中沉默它的表观遗传调节。我们将讨论一些常见的表观遗传机制以及它们如何影响HERV表达，并详细讨论HERV在干细胞、胎盘和癌症生物学中的作用。
Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology.