Epigenetic regulation of transcription and splicing of syncytins, fusogenic glycoproteins of retroviral origin

Trejbalová, Kateřina; Blažková, Jana; Matoušková, M; Kučerová, Dana; Pecnová, Ľubomíra; Vernerová, Zdeňka; Heráček, Jiří; Hirsch, Ivan; Hejnar, Jiřı́

doi:10.1093/nar/gkr562

Cited by 42 publications

(48 citation statements)

References 56 publications

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“…In contrast, few studies have looked at the interaction of HDACs with HERV LTRs. One study used ChIP to show that histone H3 acetylation was critical to the expression of HERV-W and HERV-FRD env in placental tissues, where they are known to have biological roles [30]. However, in non-placental tissues transcription is suppressed by histone H3 methylation and inefficient splicing [30].…”

Section: Higher Concentrations Of the Hdac Inhibitors Do Not Up-regulmentioning

confidence: 99%

“…One study used ChIP to show that histone H3 acetylation was critical to the expression of HERV-W and HERV-FRD env in placental tissues, where they are known to have biological roles [30]. However, in non-placental tissues transcription is suppressed by histone H3 methylation and inefficient splicing [30]. Histone H3 acetylation was detectable in a placental cell line but not in HeLa cells, corresponding to transcriptional activation in the placenta but suppression elsewhere.…”

Section: Higher Concentrations Of the Hdac Inhibitors Do Not Up-regulmentioning

confidence: 99%

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Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results:In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions:We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.

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Section: Higher Concentrations Of the Hdac Inhibitors Do Not Up-regulmentioning

confidence: 99%

Section: Higher Concentrations Of the Hdac Inhibitors Do Not Up-regulmentioning

confidence: 99%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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“…The assay for the ERVWE1 locus previously described (17) was used to determine the levels of ERVWE1 exon transcripts. Assays described previously (26) were used to determine the levels of nonspliced and spliced ERVWE1 transcripts. Threshold cycle (C T ) values from the exponential phase of the qPCR amplification plot for each target transcript were normalized to those for the gene encoding ␤-actin (see reference 38).…”

Section: Cell Culture and Influenza A/wsn/33 Virus Infections Of Cultmentioning

confidence: 99%

“…In addition to tissue-restricted expression of transcription factors, CpG methylation (24,25) and histone modifications (26) contribute to repression of ERVWE1 and other HERV-W loci. An increasing body of literature suggests that viral infections can modify the methylation status of host DNA in cells of rat and human origin (27)(28)(29)(30).…”

mentioning

confidence: 99%

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

Nellåker

Sabunciyan

et al. 2014

J Virol

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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.

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“…Expression of these fusogenic proteins is tightly restricted to placental trophoblast cells. It has been shown that these genes are silenced in somatic cells by DNA methylation of CpGs within 5' long terminal repeats (LTRs) (Matousková et al, 2006;Trejbalová et al, 2011). Aberrant methylation of these 5' LTRs in trophoblast cells might lead to the inadequate formation of the syncytiotrophoblast and a malfunctioning placenta.…”

Section: Gene Regulation By Dna Methylation In the Trophoblast Cell Lmentioning

confidence: 99%

DNA methylation and its role in the trophoblast cell lineage

Tanaka¹,

Nakanishi²,

Shiota³

2014

Int. J. Dev. Biol.

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DNA methylation functions as cellular memory beyond generations of cells and is involved in many biological processes. Because of its relatively stable nature compared with the transcriptome, the DNA methylation profile of cells can also be used to evaluate developmental similarity and cellular phenotypes. Recent insights into 5-hydroxymethylcytosine have started to reshape our view of the epigenetic regulation of mammalian development. Both global DNA methylation and hydroxymethylation levels change dynamically during preimplantation embryogenesis. It is known that DNA methylation plays an essential role in embryonic cell fate restriction, whereas its role in trophoblast development requires further research. Two distinct blastocyst-derived stem cell lines, embryonic stem (ES) cells and trophoblast stem (TS) cells, are used to study the epigenetic mechanisms underlying cell lineage maintenance and the regulation of cell differentiation. Such studies will allow us to understand the details of the epigenetic landscape of trophoblast development, which should offer valuable information for managing pregnancy-related diseases in humans.

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Epigenetic regulation of transcription and splicing of syncytins, fusogenic glycoproteins of retroviral origin

Cited by 42 publications

References 56 publications

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

DNA methylation and its role in the trophoblast cell lineage

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