Abstract
BackgroundIncreased transcription of the human endogenous retrovirus group HERV-K (HML-2) is often seen during disease. Although the mechanism of its tissue-specific activation is unclear, research shows that LTR CpG hypomethylation alone is not sufficient to induce its promoter activity and that the transcriptional milieu of a malignant cell contributes, at least partly, to differential HML-2 expression.ResultsWe analyzed the relationship between LTR sequence variation and promoter expression patterns in human breast cancer cell lines, finding them to be positively correlated. In particular, two proviruses (3q12.3 and 11p15.4) displayed increased activity in almost all tumorigenic cell lines sampled. Using a transcription factor binding site prediction algorithm, we identified two unique binding sites in each 5′ LTR that appeared to be associated with inducing promoter activity during neoplasia. Genomic analysis of the homologous proviruses in several non-human primates indicated post-integration genetic drift in two transcription factor binding sites, away from the ancestral sequence and towards the active form. Based on the sequences of 2504 individuals from the 1000 Genomes Project, the active form of the 11p15.4 site was found to be polymorphic within the human population, with an allele frequency of 51%, whereas the activating mutation in the 3q12.3 provirus was fixed in humans but not present in the orthologous provirus in chimpanzees or gorillas.ConclusionsThese data suggest that stage-specific transcription factors at least partly contribute to LTR promoter activity during transformation and that, in some cases, transcription factor binding site polymorphisms may be responsible for the differential HML-2 expression often seen between individuals.
Highlights
Increased transcription of the human endogenous retrovirus group HERV-K (HML-2) is often seen during disease
RNA sequence analysis of cells in an in vitro mammary carcinogenesis model shows that long terminal repeats (LTRs)-driven transcription of HML-2 proviruses is restricted to tumorigenic human mammary epithelial cells (HMECs), suggesting that stage-specific transcription factors appearing during malignant transformation play a role in LTR activation [32]
Differential HML‐2 promoter expression is correlated with 5′ LTR sequence similarity The HML-2 5′ LTR contains all elements necessary for driving transcription
Summary
Increased transcription of the human endogenous retrovirus group HERV-K (HML-2) is often seen during disease. Retroviruses are unique in that they are the only virus family known to exist in both endogenous and exogenous forms [1, 2]. Their integrated DNA sequences, known as proviruses, include at least four genes (gag, pro, pol, and env) flanked by long terminal repeats (LTRs), which. Recent studies show human endogenous retrovirus (HERV) expression to be increased in human embryonic stem cells (hESCs) and human preimplantation embryos and to play a critical role during embryogenesis through the maintenance of pluripotency and hESC identity [15,16,17,18,19]. Increased expression of HERV proteins was found to be correlated with increased IFITM1 expression, resulting in viral immunoprotection during human embryogenesis [19, 20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
