Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus
(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 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. We here report qPCR 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 up-regulated
in response to influenza A/WSN/33 virus infection in non-placental
cells. Knock-down of GCM1 by siRNA, 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
methytransferase SETDB1 levels along with viral 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.Importance Syncytin-1, a protein encoded by the env gene in the
HERV-W locus ERVWE1 appears crucial for the development and functioning
of the human placenta and is transcriptionally repressed in
non-placental 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 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 aberrant
transcription of HERV-W loci.
(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 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. We here report qPCR 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 up-regulated
in response to influenza A/WSN/33 virus infection in non-placental
cells. Knock-down of GCM1 by siRNA, 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
methytransferase SETDB1 levels along with viral 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.Importance Syncytin-1, a protein encoded by the env gene in the
HERV-W locus ERVWE1 appears crucial for the development and functioning
of the human placenta and is transcriptionally repressed in
non-placental 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 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 aberrant
transcription of HERV-W loci.
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