Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

Abstract

Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements. IMPORTANCESyncytin-1, a protein encoded by the env gene in the HERV-W locus ERVWE1, appears to be crucial for the development and functioning of the human placenta and is transcriptionally repressed in nonplacental tissues. Nevertheless, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. In the present paper, we report findings suggesting that an exogenous influenza A virus infection can transactivate ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. These observations have implications of potential relevance for viral pathogenesis and for conditions associated with the aberrant transcription of HERV-W loci.

Pathophysiological Role of HERV-W in Schizophrenia

“…Elements with intact long terminal repeats as well as those elements flanked by truncated long terminal repeats were expressed and regulated secondary to the virus infection. Findings recently reported by Li et al 66 suggest that an exogenous influenza A virus infection can transactivate HERV-W element ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. Perron et al 67 demonstrated that in vitro infection of leptomeningeal cells in patients with multiple sclerosis with herpes simplex virus type 1 results in potent stimulation of the specific reverse transcriptase activity and coexpression of both herpes simplex virus type 1 virions and retrovirus-like particles.…”

Molecular functions of human endogenous retroviruses in health and disease

“…Flow cytometry data showed increased percentages of cells exposing surface HERV-W (ERVW-1) Env protein, that occur differently in specific cell subsets, and in acute disease and past infection [174]. Expression of the same retroviral protein was considerably increased in various human cell types following influenza A virus infection [2]. Importantly, treatment with neuroleptics and antidepressants (e.g., valproic acid, haloperidol, risperidone, and clozapine) may greatly upregulate the expression of HERV-W (ERVW-1) and ERV9 elements in CNS cells [176].…”

“…Genomic copies of HERVs are of particular interest because in addition to functional viral genes, they have multitude of regulatory DNA regions serving as promoters [1][2][3], enhancers [4,5], polyadenylation signals [6,7], insulators [8,9] and binding sites for various nuclear proteins [2,[10][11][12][13]. Many families of HERVs exhibit high transcriptional activity in human tissues [1,[14][15][16][17].…”

A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis

“…Certain copies of the HERV elements are activated by some infectious agents. For example, T. gondii and the influenza virus may activate HERV-W elements within human cell lines (Frank et al, 2006; Li et al, 2014; Nellaker et al, 2006). Several studies including a meta-analysis have indicated an increased prevalence of antibodies against T. gondii in schizophrenia (Torrey et al, 2007, 2012).…”