Viral influencers: deciphering the role of endogenous retroviral LTR12 repeats in cellular gene expression

The human genome is like a museum of ancient retroviral infections. It contains a large number of endogenous retroviruses (ERVs) that bear witness to past integration events. About 5,000 of them are so-called long terminal repeat 12 (LTR12) elements. Compared with 20,000 human genes, this is a remarkable number. Although LTR12 elements can act as promoters or enhancers of cellular genes, the function of most of these retroviral elements has remained unclear. In our mini-review, we show that different LTR12 elements share many similarities, including common transcription factor binding sites. Furthermore, we summarize novel insights into the epigenetic mechanisms governing their silencing and activation. Specific examples of genes and pathways that are regulated by LTR12 loci are used to illustrate the regulatory network built by these repetitive elements. A particular focus is on their role in the regulation of antiviral immune responses, tumor cell proliferation, and senescence. Finally, we describe how a targeted activation of this fascinating ERV family could be used for diagnostic or therapeutic purposes.