Human endogenous retroviruses: friend or foe?

Weiss, Robin A.

doi:10.1111/apm.12476

Cited by 34 publications

(24 citation statements)

References 78 publications

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“…Much like DNA transposons, almost all HERVs are mutated and cannot retrotranspose in humans. 10,18 However, sequences within HERVs influence host gene expression in the early embryo, 19 and HERV-derived proteins are important for placental development. 20 Moreover, stretches of DNA derived from endogenous retroviruses have shaped, over evolutionary time, a transcriptional network involved in the interferon response of innate immunity.…”

Section: Mobile Dna In Humansmentioning

confidence: 99%

Mobile DNA in Health and Disease

Kazazian¹,

2017

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Section: Mobile Dna In Humansmentioning

confidence: 99%

Mobile DNA in Health and Disease

Kazazian¹,

2017

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“…As a result, the fate of most ERVs is gradual genetic degradation through mutation and homologous recombination. Nevertheless, a minority of ERVs retain a whole or partially intact open reading frame potentially capable of producing a functional protein (Weiss 2016). This point is particularly salient in regard to the placenta, which in many species express a range of ERVs that are involved in trophoblast function (Denner 2016).…”

Section: Evolution Of Placenta Specific Genesmentioning

confidence: 99%

The evolution of the placenta

Roberts¹,

Green²,

Schulz³

2016

Reproduction

174

125

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The still apt definition of a placenta is that coined by Mossman, namely apposition or fusion of the fetal membranes to the uterine mucosa for physiological exchange. As such it is a specialized organ whose purpose is to provide continuing support to the developing young. By this definition, placentas have evolved within every vertebrate class other than birds. They have evolved on multiple occasions, often within quite narrow taxonomic groups. As the placenta and the maternal system associate more intimately, such that the conceptus relies extensively on maternal support, the relationship leads to increased conflict that drives adaptive changes on both sides. The story of vertebrate placentation, therefore, is one of convergent evolution at both the macro- and molecular levels. In this short review, we first describe the emergence of placental-like structures in non-mammalian vertebrates and then transition to mammals themselves. We close the review by discussing mechanisms that might have favored diversity and hence evolution of the morphology and physiology of the placentas of eutherian mammals.

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“…This greatly extends the possible therapeutic rationale for the use of HMAs in solid tumors. However, it has to be mentioned that the reactivation of ERVs by HMA treatment might increase genomic instability, resulting in acquisition of new mutations, disease progression, immune evasion, and development of drug resistance [105]. …”

Section: Hmas (Re)induce Expression Of Genes Associated With Antitumomentioning

confidence: 99%

The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

et al. 2017

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Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Although the global demethylation of DNA by HMAs can induce anti-tumor effects, it can also upregulate the expression of inhibitory immune checkpoint receptors and their ligands, resulting in secondary resistance to HMAs. Recent studies have, however, suggested that this could be exploited to prime or (re)sensitize tumors to immune checkpoint inhibitor therapies. In recent years, immune checkpoints have been targeted by novel therapies, with the aim of (re)activating the host immune system to specifically eliminate malignant cells. Antibodies blocking checkpoint receptors have been FDA-approved for some solid tumors and a plethora of clinical trials testing these and other checkpoint inhibitors are under way. This review will discuss AZA and DAC novel mechanisms of action resulting from the re-expression of pathologically hypermethylated promoters of gene sets that are related to interferon signaling, antigen presentation and inflammation. We also review new insights into the molecular mechanisms of action of transient, low-dose HMAs on various tumor types and discuss the potential of new treatment options and combinations.

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Human endogenous retroviruses: friend or foe?

Cited by 34 publications

References 78 publications

Mobile DNA in Health and Disease

Mobile DNA in Health and Disease

The evolution of the placenta

The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

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