Emerging roles for endogenous retroviruses in immune epigenetic regulation

Abstract

In recent years, there has been significant progress toward understanding the transcriptional networks underlying mammalian immune responses, fueled by advances in regulatory genomic technologies. Epigenomic studies profiling immune cells have generated detailed genome-wide maps of regulatory elements that will be key to deciphering the regulatory networks underlying cellular immune responses and autoimmune disorders. Unbiased analyses of these genomic maps have uncovered endogenous retroviruses as an unexpected ally in the regulation of human immune systems. Despite their parasitic origins, studies are finding an increasing number of examples of retroviral sequences having been co-opted for beneficial immune function and regulation by the host cell. Here, we review how endogenous retroviruses have given rise to numerous regulatory elements that shape the epigenetic landscape of host immune responses. We will discuss the implications of these elements on the function, dysfunction, and evolution of innate immunity.

Keywords: comparative immunology/evolution; gene regulations; transcription factors; viral.

FIGURE 1.

Retroviruses become endogenized and retain potential for regulatory activity. (A) Retroviruses are integrated into host cell DNA during infection. They become endogenous when they are integrated into germline DNA and passed on vertically to progeny. (B) Endogenous retroviruses disperse throughout the host cell genome. ERV families may include hundreds or thousands of individual insertion events. (C) ERVs often lose the ability to transpose and encode proteins through mutational decay, or recombination of LTRs. (D) Examples of ERV epigenetic status. Most ERVs are epigenetically silenced by DNA methylation and repressive histone modifications. Some ERVs have active promoter function, are marked by promoter-associated histone modifications, and provide the transcription start site for mRNA transcripts. Many ERVs have enhancer activity and are marked by enhancer-associated histone modifications and transcription factors. Some ERVs may function as insulators, associated with CTCF binding and are localized at boundaries between epigenetically active and silenced domains. Created with BioRender

FIGURE 2.

Examples of co-opted ERV and transposon elements have been identified with a variety of regulatory functions. (A) An interferon-inducible alternative promoter in the ACE2 gene in humans derived from an LTR16 and a MIRb element gives rise to a nonfunctional truncated isoform during IFN signaling 85. (B) A MER41-derived enhancer upstream of the AIM2 gene in humans is bound by the interferon signaling transcription factor STAT1 and is necessary for interferon-dependent expression of AIM2 10. (C) The non-ERV retrotransposon family MIR has been attributed with insulator activity enriched in T cell–specific gene regions. MIRs recruit RNA Polymerase III (PolIII) complexes and delineate regions of active and repressive epigenetic regulation 35

FIGURE 3.

Retroviruses both antagonize and facilitate rapid evolution of host immunity. Retroviruses drive evolution of host immunity both as pathogens and as a source of novel DNA. They occasionally endogenize and become co-opted for the benefit of the host. Cooption of ERVs is particularly prevalent in the immune system and allows for rapid reorganizing of the host immune regulatory networks in the ongoing arms race with exogenous viruses and other pathogens. Created with BioRender