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Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.

Young GR, Mavrommatis B, Kassiotis G - Retrovirology (2014)

Bottom Line: Modulated REs were frequently found near or embedded within similarly-modulated host genes.In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans.More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK. gkassio@nimr.mrc.ac.uk.

ABSTRACT

Background: A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs accumulate inactivating mutations or deletions and thus lose the ability to replicate. Additionally, REs can be transcriptionally repressed by dedicated mechanisms of the host. Nevertheless, many of them still possess and express intact open reading frames, and their transcriptional activity has been associated with many physiological and pathological processes of the host. However, this association remains tenuous due to incomplete understanding of the mechanism by which RE transcription is regulated. Here, we use a bioinformatics tool to examine RE transcriptional activity, measured by microarrays, in murine and human immune cells responding to microbial stimulation.

Results: Immune cell activation by microbial signals in vitro caused extensive changes in the transcription not only of the host genes involved in the immune response, but also of numerous REs. Modulated REs were frequently found near or embedded within similarly-modulated host genes. Focusing on probes reporting single-integration, intergenic REs, revealed extensive transcriptional responsiveness of these elements to microbial signals. Microbial stimulation modulated RE expression in a cell-intrinsic manner. In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans.

Conclusions: Together, these results highlight the utility of improved methodologies in assessing RE transcription profiles in both archived and new microarray data sets. More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription. RE responsiveness to external stimuli should, therefore, be considered in any association between RE transcription and disease.

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Related in: MedlinePlus

RE expression in human disease. Hierarchally-clustered heatmaps of RE-reporting probes significantly regulated between conditions (p < 0.01 by ANOVA comparing conditions and eliminating age and gender) for human influenza A (A), HIV-1 infection (B), and ulcerative colitis (C). Respectively, data are from E-GEOD-6269 (a Human Genome U133A array sampling peripheral blood), and two Human Genome U133 Plus arrays, E-GEOD-16363 (sampling lymph node biopsies), and E-GEOD-38713 (sampling gut biopsies). Where present, probes corresponding to HML-2 elements are highlighted.
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Fig7: RE expression in human disease. Hierarchally-clustered heatmaps of RE-reporting probes significantly regulated between conditions (p < 0.01 by ANOVA comparing conditions and eliminating age and gender) for human influenza A (A), HIV-1 infection (B), and ulcerative colitis (C). Respectively, data are from E-GEOD-6269 (a Human Genome U133A array sampling peripheral blood), and two Human Genome U133 Plus arrays, E-GEOD-16363 (sampling lymph node biopsies), and E-GEOD-38713 (sampling gut biopsies). Where present, probes corresponding to HML-2 elements are highlighted.

Mentions: Previous work has identified the potential regulation of HERV-W family proviruses by influenza A [48]. To further translate the impact of influenza infection on the expression of murine REs to a human system, a comparative analysis of a human microarray dataset was made. This revealed a smaller effect of influenza infection (Figure 7A). Many fewer REs were significantly regulated, with similar numbers induced and repressed. The relatively small number of regulated elements found, whilst likely a factor of the size of the microarray platform used, may also be due to sampling peripheral blood, which might not reflect the full extent of disease activity in the target organ (lung).


Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.

Young GR, Mavrommatis B, Kassiotis G - Retrovirology (2014)

RE expression in human disease. Hierarchally-clustered heatmaps of RE-reporting probes significantly regulated between conditions (p < 0.01 by ANOVA comparing conditions and eliminating age and gender) for human influenza A (A), HIV-1 infection (B), and ulcerative colitis (C). Respectively, data are from E-GEOD-6269 (a Human Genome U133A array sampling peripheral blood), and two Human Genome U133 Plus arrays, E-GEOD-16363 (sampling lymph node biopsies), and E-GEOD-38713 (sampling gut biopsies). Where present, probes corresponding to HML-2 elements are highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222864&req=5

Fig7: RE expression in human disease. Hierarchally-clustered heatmaps of RE-reporting probes significantly regulated between conditions (p < 0.01 by ANOVA comparing conditions and eliminating age and gender) for human influenza A (A), HIV-1 infection (B), and ulcerative colitis (C). Respectively, data are from E-GEOD-6269 (a Human Genome U133A array sampling peripheral blood), and two Human Genome U133 Plus arrays, E-GEOD-16363 (sampling lymph node biopsies), and E-GEOD-38713 (sampling gut biopsies). Where present, probes corresponding to HML-2 elements are highlighted.
Mentions: Previous work has identified the potential regulation of HERV-W family proviruses by influenza A [48]. To further translate the impact of influenza infection on the expression of murine REs to a human system, a comparative analysis of a human microarray dataset was made. This revealed a smaller effect of influenza infection (Figure 7A). Many fewer REs were significantly regulated, with similar numbers induced and repressed. The relatively small number of regulated elements found, whilst likely a factor of the size of the microarray platform used, may also be due to sampling peripheral blood, which might not reflect the full extent of disease activity in the target organ (lung).

Bottom Line: Modulated REs were frequently found near or embedded within similarly-modulated host genes.In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans.More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK. gkassio@nimr.mrc.ac.uk.

ABSTRACT

Background: A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs accumulate inactivating mutations or deletions and thus lose the ability to replicate. Additionally, REs can be transcriptionally repressed by dedicated mechanisms of the host. Nevertheless, many of them still possess and express intact open reading frames, and their transcriptional activity has been associated with many physiological and pathological processes of the host. However, this association remains tenuous due to incomplete understanding of the mechanism by which RE transcription is regulated. Here, we use a bioinformatics tool to examine RE transcriptional activity, measured by microarrays, in murine and human immune cells responding to microbial stimulation.

Results: Immune cell activation by microbial signals in vitro caused extensive changes in the transcription not only of the host genes involved in the immune response, but also of numerous REs. Modulated REs were frequently found near or embedded within similarly-modulated host genes. Focusing on probes reporting single-integration, intergenic REs, revealed extensive transcriptional responsiveness of these elements to microbial signals. Microbial stimulation modulated RE expression in a cell-intrinsic manner. In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans.

Conclusions: Together, these results highlight the utility of improved methodologies in assessing RE transcription profiles in both archived and new microarray data sets. More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription. RE responsiveness to external stimuli should, therefore, be considered in any association between RE transcription and disease.

Show MeSH
Related in: MedlinePlus