Systems Biology to Understand and Regulate Human Retroviral Proinflammatory Response

Abstract

The majority of human genome are non-coding genes. Recent research have revealed that about half of these genome sequences make up of transposable elements (TEs). A branch of these belong to the endogenous retroviruses (ERVs), which are germline viral infection that occurred over millions of years ago. They are generally harmless as evolutionary mutations have made them unable to produce viral agents and are mostly epigenetically silenced. Nevertheless, ERVs are able to express by still unknown mechanisms and recent evidences have shown links between ERVs and major proinflammatory diseases and cancers. The major challenge is to elucidate a detailed mechanistic understanding between them, so that novel therapeutic approaches can be explored. Here, we provide a brief overview of TEs, human ERVs and their links to microbiome, innate immune response, proinflammatory diseases and cancer. Finally, we recommend the employment of systems biology approaches for future HERV research.

Transposable Elements and Human Diseases: Mechanisms and Implication in the Response to Environmental Pollutants

“…Therefore, improving our knowledge of TEs through deep genomic approaches may lead to new potential diagnostic markers of diseases and prenatal markers of genetic diseases. Thus, the development of combined molecular (i.e., next generation sequencing and whole genome sequencing) and bioinformatics tools is of great interest despite mostly used in the cancer field [ 32 , 34 , 50 , 55 , 56 , 113 , 130 , 167 , 168 , 169 ]. Finally, the exposure of individuals to numerous stresses and in particular to environmental pollutants and contaminants seems to have a non-negligible impact on the epigenetic derepression and mobility of TEs, which can lead in this way to the development of certain pathologies such as cancers, neurological or autoimmune diseases.…”

“…Indeed, these authors observed TE dysregulation in the alveolar type II lung cells and alveolar macrophages of IPF patients and the increased TE, especially LINE-1, expression is positively correlated with both the activation of cellular TE inhibitors and the innate immune response and negatively correlated with autophagy in IPF [ 129 ]. The involvement of HERVs in innate immunity has been also demonstrated and HERVs contribute to pro-inflammatory diseases such as Type-I diabetes, autoimmune disorders and multiple sclerosis, as well as neuropathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [ 130 ]. Finally, the mutual interaction between microbiote and HERVs expression was highlighted in humans by a strong correlation between the expression of HERV-H, -K and -W, and the concentration of Bifidobacterium spp.…”

“…Finally, the mutual interaction between microbiote and HERVs expression was highlighted in humans by a strong correlation between the expression of HERV-H, -K and -W, and the concentration of Bifidobacterium spp. in the gut [ 130 , 131 ]. Moreover, the expression of ERVs was found to be favored by the skin microbiota as shown by using mouse keratinocyte model challenged by various skin commensals [ 132 ].…”

CHMP4A stimulates CD8+ T‐lymphocyte infiltration and inhibits breast tumor growth via the LSD1/IFNβ axis

“…7 Human endogenous retroviruses (HERVs) are found in human genomes because of retrovirus integration over millions of years ago. 8 Ancient HERV elements contribute to human genomic innovation and human evolution and have recently been identified as regulators in various pathophysiological processes, such as immune-related diseases, cancers, and neurological disorders. 9 Lysine demethylase 1A (LSD1/KDM1A) is reported to negatively regulate HERV transcripts and their intracellular double-stranded RNA (dsRNA), which is one type of PAMPs stimulating IFNβ producion.…”

“…Human endogenous retroviruses (HERVs) are found in human genomes because of retrovirus integration over millions of years ago 8 9 .…”