Epigenetic dynamics of Human Endogenous Retroviruses (HERVs) in human cancer cell lines

Transposable elements (TEs) are endogenous components of eukaryotic genomes, constituting 45% of human DNA. The human genome project revealed that human endogenous retroviruses (HERVs) constitute about 8% of the sequence. HERVs are derived from sequences integrated into germ cells during retrovirus infections, up to 25 million years ago. However, most copies of HERVs are defective in multiple ways. The HERV-K family is the youngest family and likely has significant biological activity because of its protein coding capacity. HERV-K activity may be involved in a variety of cancers, and in particular may play an important role in human melanoma. In this project, HERV activity in melanoma and different cancer cell lines was investigated. Our results showed the HERV-K pol gene is expressed in melanoma and in breast, prostate and colon cancers. Furthermore, the response to serum starvation conditions is not simply related to increased expression of HERV-K genes, and changes in cellular phenotype under serum starvation are limited to particular melanoma cell lines, rather than being a general phenomenon. HERV-K env protein expression in melanoma cells was compared to normal primary melanocytes - 1% FBS serum starvation can increase expression of this protein in SKMel5 cells that retain an adherent phenotype. Moreover, env protein expression is significantly increased in T47D breast cancer cells under 1% FBS. The analysis of HERV-K LTR methylation state demonstrated that HERV K env and gag proteins in melanoma cells under 10% FBS and 1% FBS conditions decreased. The most interesting finding was the detection of 98 candidate loci as novel proviral insertions where previously these loci were annotated as solo LTRs. This result suggests that proviruses are systematically excluded from assemblies and the census of HERV-K proviruses is much greater than represented in assembled genomes. The Genome-wide amplification of proviral sequences combined with Next Generation Sequences (GAPS –NGS) is established as an effective approach to discover new proviral loci.