Molecular functions of human endogenous retroviruses in health and disease

Abstract

Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

Human Endogenous Retroviruses

“…According to the same study, HERV-E encoded epitope was targeted by antitumor cytotoxic lymphocytes thus demonstrating the importance of anti-HERV immune response in the progression or regression of human diseases (Takahashi et al, 2008;Suntsova et al, 2015 gene belonging to HERV-FRD encodes syncytin-2, which contributes to syncytiotrophoblast formation and has a role in immune tolerance of the foetus. Reduced expression of both syncytin-1 and -2 was associated higher risk of pre-eclampsia (Hurst and Magiorkinis, 2017;Lerat and Semon 2007;Yi et al, 2004).…”

“…Many transcription regulating elements including transcription initiating and terminating signals are located in LTR sequences. The LTR serves as enhancers (Suntsova et al, 2013), promoters (Buzdin et al, 2006), polyadenylation signals (Suntsova et al, 2015) and binding sites for several nuclear proteins (Schulman et al, 2010). These structures are comparatively frequent in the human genome and it is assumed that they influenced evolution of the primate genome via transposition, translocation and recombination (Paces et al, 2013).…”

“…HERVs and autoimmune diseases association appeared by increased proviral transcript levels and finding anti-HERV protein antibodies from patient having autoimmune disorders (Bannert and Kurth, 2004). In systemic lupus erythematosus (SLE) HERV-E mRNA expression was higher in lupus CD4+ T cells when compared to the healthy controls (Suntsova et al, 2015). In patients with rheumatoid arthritis, there is a significant increase in IgG antibody against to HERV-K10 gag protein as compared to control group (Nelson et al, 2014).…”

On the Concept Of Retrotransposons: Controlling Genome and Making Stress Memories

“…A flourish of works has documented the involvement of retrotransposons in embryogenesis, cell differentiation, pluripotency, cell cycle, DNA repair, aging, genomic imprinting, X-chromosome inactivation, behavior, metabolism and immune responses [42,91,[124][125][126][127][128][129][130][131][132][133][134][135][136][137] . However, besides their beneficial impact on host cell, the perturbation and/or loss of cellular control mechanisms may lead to the onset of genetic or multifactorial diseases [80,138,139] . So far, it is known that retrotransposon activity, concerning their transcription and retrotransposition, is induced during cellular processes among them cell proliferation and differentiation, as well as by numerous stress factors such as heavy metals, oxidative stress, UV irradiation, viral infection, and drugs [1,12,74,91,128,[140][141][142][143][144] .…”

Retrotransposons and Complex Diseases: Is it Time for a Retrotransposon- Based “Omics” Profiling approach to Elucidate the Origins of Pathogenesis?

“…Controlled retrotransposon activity might be beneficial for the cell in terms of genetic and/or epigenetic regulation of gene expression, adaptation and homeostasis upon environmental challenges [3]. On the flip side, in some cases, their deregulated state may be noxious causing monogenic or complex (multifactorial) genetic diseases [5][6][7].…”