Abstract
BackgroundAberrant expression of human endogenous retrovirus (HERV) elements in the W family has previously been associated with schizophrenia, multiple sclerosis and preeclampsia. Little is know regarding the basal expression, transcriptional regulation and functional significance of individual HERV-elements. Since viral infections have previously been reported to transactivate retroviral long terminal repeat regions we examined the basal expression of HERV-W elements and following infections by influenza A/WSN/33 and Herpes simplex 1 viruses in human cell-lines.MethodsRelative levels of transcripts encoding HERV-W elements and cellular genes were analyzed by qPCR methods. An analysis of amplicon melting temperatures was used to detect variations in the frequencies of amplicons in discrete ranges of such melting temperatures. These frequency-distributions were taken as proxy markers for the repertoires of transcribed HERV-W elements in the cells.ResultsWe report cell-specific expression patterns of HERV-W elements during base-line conditions. Expressed elements include those with intact regulatory long terminal repeat regions (LTRs) as well as elements flanked by truncated LTRs. Subsets of HERV-W elements were transactivated by viral infection in the different cell-lines. Transcriptional activation of these elements, including that encoding syncytin, was dependent on viral replication and was not induced by antiviral responses. Serum deprivation of cells induced similar changes in the expression of HERV-W elements suggesting that the observed phenomena are, in part, an effect of cellular stress.ConclusionWe found that HERV-W elements, including elements lacking regulatory LTRs, are expressed in cell-specific patterns which can be modulated by environmental influences. This brings into light that mechanisms behind the regulation of expression of HERV-W elements are more complex than previously assumed and suggests biological functions of these transcripts.
Highlights
Aberrant expression of human endogenous retrovirus (HERV) elements in the W family has previously been associated with schizophrenia, multiple sclerosis and preeclampsia
Virus infection transactivates HERV-W elements Initially, the neuroepithelioma cell-line (SK-N-MC) was infected with increasing titers of herpes simplex virus 1 (HSV-1) or influenza A/WSN/33 viruses. 24 or 48 hours post infection, the levels of transcripts from the latency gene 1 of HSV-1 and segment 8 of the influenza A/WSN/ 33 virus genomes were proportional to the respective numbers of viral plaque forming units added to the cultures as determined by quantitative real-time PCR (Figure 1A and Figure 1B)
Cells infected with influenza A/WSN/33 virus responded with a dose-dependent increase in the relative levels of HERV-W env, but not gag, transcripts (Figure 1B)
Summary
Aberrant expression of human endogenous retrovirus (HERV) elements in the W family has previously been associated with schizophrenia, multiple sclerosis and preeclampsia. Since viral infections have previously been reported to transactivate retroviral long terminal repeat regions we examined the basal expression of HERV-W elements and following infections by influenza A/WSN/33 and Herpes simplex 1 viruses in human cell-lines. According to Pavlicek et al [9] the human genome contains 654 HERV-W elements, the majority of which are comprised of long terminal repeat regions (LTR) lacking internal sequence. 149 pseudoelements with internal sequences were found, lacking the regulatory U3 region of the 5'-LTR and the U5 region of the 3'-LTR These copies resemble retroviral mRNAs and are thought to originate from LINE-mediated reverse transcription of such mRNAs. The remaining elements were grouped together in a third category based on lack of diagnostic regions due to truncations [9]. Potential regulation of individual HERV-W element expression is even less studied
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