Human Endogenous Retroviruses as Gene Expression Regulators: Insights from Animal Models into Human Diseases

Abstract

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

“…In terms of pathophysiological mechanisms insights, it is of interest that several recent reports highlight the potential interfering effects of exogenous infections (i.e. SARS-Cov-2) on human endogenous retroviruses (HERVs), that may undergo activation leading in turn to inflammatory and immune responses ( Durnaoglu et al, 2021 ). During COVID-19 infection, genes belonging to different HERVs families (i.e.…”

Differential expression of an endogenous retroviral element [HERV-K(HML-6)] is associated with reduced survival in glioblastoma patients

“…HERV elements are identifiable by the presence of established retroviral genes: gag (core structural proteins), pol (viral replication enzymes including reverse transcriptase), pro (viral protease), env (envelope protein) and LTR (Long Terminal Repeats). In most differentiated cells, HERVs have lost their innate ability to form active viruses and replicate due to a combination of single nucleotide polymorphisms, coding deletions and mutations, but may nevertheless play roles in multiple physiological processes, including stem cell pluripotency, cell proliferation, and cell survival largely through their cis -regulatory elements found in their LTRs 1 , 2 .…”

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

“…HERV are residues of viral infections from the past that have remained in the human genome and occupy about 8% of it. Complete HERV elements ( Figure 1 ) have a length of 1-10Kb and contains the ORF of four viral-like genes: gag, pol, env, pro encoding respectively the viral capsid protein, the reverse transcriptase, the envelope-associated glycoprotein and the viral protease ( 4 ). 5’ and 3’ LTR control the bidirectional transcription by RNAP2 of HERV elements ( 5 ), their polyadenylation ( 6 ) and chromatin folding ( 7 ).…”