Abstract
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.
Highlights
The human genome is littered with endogenous retroelements, including non-long-terminal repeat (LTR) elements such as long interspersed nuclear repeats (LINEs) and short interspersed nuclear repeats (SINEs), as well as the long-terminal repeats (LTR)-containing endogenous retroviruses (ERVs).It is widely accepted that retroelements are subject to repression by both genetic and epigenetic mechanisms
Control of human ERVs (HERVs) and 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
It is usual for CpG nucleotides to be methylated throughout the human genome, including those found in HERVs; exceptions to this, referred to as CpG islands (CGIs), are sites of low methylation that are frequently found near active genes and enhancer elements [35]
Summary
The human genome is littered with endogenous retroelements, including non-long-terminal repeat (LTR) elements such as long interspersed nuclear repeats (LINEs) and short interspersed nuclear repeats (SINEs), as well as the long-terminal repeats (LTR)-containing endogenous retroviruses (ERVs). Tumorigenic insertional mutagenesis is more likely to happen when more cells have ERV proliferation [2] It seems that a complete knock-out of the ERVs (e.g., through deleterious mutations) would be the safest option for the host but this would lead to a complete extinction of ERVs. Intuitively, the “sweet spot” of ERV activity that allows both ERVs and host survival could be a window of activity near early life stages (e.g., germline and embryonic stem cells) where the number of cells is irrelevant to the final body size of the host, followed by silencing in somatic tissues. We will describe some of the recent findings on the regulation of ERVs by epigenetics, emphasising studies on human ERVs (HERVs) in normal tissues and in diseases
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