A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs)

Brütting, Christine; Emmer, Alexander; Kornhuber, Malte; Staege, Martin S.

doi:10.1007/s11033-016-4004-0

Cited by 20 publications

(11 citation statements)

References 77 publications

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“…Though mutations have silenced the expression of the majority of these elements, approximately 7% of all known ERVs are transcriptionally active 22 . Moreover, mutations in these elements have been linked to diseases, including cancer 15 and multiple sclerosis 23 . Translated ERVs have been shown to play a role in lymphocyte activation, and transcribed ERVs play a role in transcriptional regulation 24 .…”

Section: Discussionmentioning

confidence: 99%

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Gensterblum

Sawalha

2017

Preprint

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The major histocompatibility complex (MHC) region encodes human leukocyte antigen (HLA) genes and is the most complex region in the human genome. The extensive polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein coding human endogenous retrovirus genes. We revealed extensive allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Further, we showed that the transcriptome within the MHC region can be defined by 14 distinct co-expression clusters, with evidence of co-regulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.

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Section: Discussionmentioning

confidence: 99%

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Gensterblum

Sawalha

2017

Preprint

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“…These analyses are by now an established method to identify risk loci linked to autoimmune conditions, but rarely take into account HERV sequences and their networking with cellular genes. As an example, MS-associated SNPs showed a significant enrichment of HERV insertion and potential HERV ORFs in their genetic neighborhood as compared to control SNPs ( 135 , 136 ). Accordingly, SNPs in the antiviral gene TRIM5 were shown to be negatively correlated to MS, while SNPs around a HERV-Fc1 locus on chromosome X had a significant association with the disease, with a risk that was strongly influenced by the two genes in an additive fashion ( 137 ).…”

Section: Hervs As Activators Of Antiviral Innate Immunitymentioning

confidence: 99%

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

2018

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About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

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“…However, in support of the proposed model, a subsequent study has established that there is a significant over-representation, among the MS-risk associated SNPs, of SNPs that are in the vicinity of HERVs [44]. This observation adds direct support for the importance of these elements in the MS disease development.…”

mentioning

confidence: 71%

Could Multiple Sclerosis Develop due to Epstein Barr Virus Infections Causing a Time-Delayed Transcriptional-Activation of Human Endogenous Retroviruses?

Dalgaard¹

2016

Adv Tech Biol Med

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The underlying cause of multiple sclerosis (MS) is not fully understood. However, it is known that Epstein Barr virus (EBV) infections pre-date the development of the disease. Here I explore whether the underlying cause of Multiple Sclerosis can be explained by an inappropriate intra-cellular transcriptional response to the integration of the EBV in the genome of neural cells. Such a re-programming is proposed to lead to the transcriptional activation of other dormant viruses, human endogenous retroviruses (HERVs), followed by the "auto-immune" response and inflammation observed in the brain of MS patients?

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A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs)

Cited by 20 publications

References 77 publications

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

Could Multiple Sclerosis Develop due to Epstein Barr Virus Infections Causing a Time-Delayed Transcriptional-Activation of Human Endogenous Retroviruses?

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