Reactivation of human endogenous retroviruses (HERVs) in carcinogenesis, immunity, stem cells and placentation
University of Yamanashi, Japan
Human endogenous retroviruses (HERVs) are fossil forms of originally infectious retrovirus sequences occupying up to 8% of the present-day human genome. The viral genetic structures have been degenerated in different degrees depending on the HERV families and chromosomal loci as the consequences of numerous chromosomal events including mutation, deletion, recombination and translocation.. As the original proviral DNA contained a repeat sequence termed ‘long terminal repeat’ (LTR) with promoter/enhancer elements at the 5’ and 3’ ends, HERVs and solo LTRs can be responsive for cellular gene disruption as well as the downstream gene activation. HERVs also provide open reading frames for virus-derived proteins, intact or fragmented, which can also influence cellular functions. Furthermore, HERVs are thought to have contributed to human evolution by mediating recombination and chromosomal rearrangements.
These hypotheses are gaining support from recent studies. Many HERVs undergo epigenetic silencing in normal cells, but are reactivated by DNA hypomethylation in cancers at many loci. Aberrantly activated MaLR family (THE1B) LTR drives colony stimulating factor receptor 1 gene expression, which offers a novel mechanism of lymphoma tumorigenesis. HERV-K, the newest family of HERV, has been most extensively studied by molecular biology. The LTR activation and HERV-K-encoded proteins have been implicated in carcinogenesis of melanoma and breast cancer. HERV-H expression seems colon cancer-specific, whereas HERV-E produces renal cancer-specific antigens. HERV-Fc1 and HERV-W may be involved in pathogenesis of multiple sclerosis and other autoimmune diseases. Importantly, the finding of infectious endogenous retroviruses (ERVs) of domestic animals suggests a risk of zoonotic infection through vaccination and xenotransplantation.
On the other hand, Syncytins, HERV/ERV-encoded envelope proteins, are essential for placental tissue development. Mouse stem cell totipotency is detected with concomitant expression of MuERV-L. Moreover, some HERV components are useful for construction of gene expression vectors and vaccination.
These varied aspects of HERV/ERV researches have taken place in different disciplines: genetics, virology, oncology, and evolutionary biology. In this plan of ‘Frontiers Research Topic’, scientists from various backgrounds will bring their basic knowledge, new findings, ideas and technologies to create a more comprehensive understanding and to promote dialogue among researchers.