Editorial Overview: Endogenous Retroviruses in Development and Disease

As guest editors, we are pleased to present this Special Issue on endogenous retroviruses (ERVs) and their impact on mammalian development and disease [...].

as outlined in detail by Fukuda and Shinkai [3]. Other epigenetic factors that cooperate with the SETDB1 complex include the well-known TRIM28/KAP1 protein and its associated KRAB zinc finger proteins; Margalit et al. [4] present new evidence demonstrating a role for additional TRIM family members, TRIM24 and TRIM33, which cooperate with TRIM28/KAP1 to regulate ERV expression in embryonic stem cells. Finally, Cullen and Schorn [5] look at post-transcriptional regulatory mechanisms and review the roles of tRNA-derived small RNA fragments (tRFs) in blocking ERV replication. In contrast to these studies that elaborate on the complexes that regulate ERVs, Enriquez-Gasca et al. [6] describe the many ways that ERV derived regulatory elements can turn the tables to regulate host gene expression.
Two articles in this issue highlight the importance of taking an evolutionary view of how ERV sequences interact with their hosts, in order to gain insight into how control mechanisms have arisen and continue to evolve. In particular, many mouse ERV loci are still active, such that ERV sequences vary both within mouse populations and across closely related mouse strains. Rebollo et al. [7] present a masterful study identifying a potential master copy of the most active known mouse ERV, intracisternal A-type particles (IAPs). Using a variety of genomic assays, they identify a single intact locus that may be the source of many new ERV insertions in the C3H strain of mice, and which appears to be present in many other mouse strains as well. Identifying these source elements, and the genetic strains in which they are active, provides a crucial background for understanding how, and in what context, ERVs evade host control mechanisms. To complement this study, Elmer and Ferguson-Smith [8] provide a timely review of how ERV control mechanisms differ across mouse strains as host genomes evolve to fight back particularly against active ERVs.
Despite the many redundant control systems designed to silence ERV activity, it is known that silencing of ERVs is imperfect, such that ERV transcriptional activity can occur in both germline and somatic cells. This has led to the hypothesis that unregulated ERV activity might contribute to human disease. To explore this idea in the context of a specific disease, Kolbe et al. [9] present a new study demonstrating that HERV-H sequences are highly expressed in samples from patients with head and neck cancer and may serve as biomarkers for disease progression. In another cancer context, Singh et al. [10] present results showing that HERV-K sequences are bound by the melanocyte lineage transcription factor MITF, and are highly expressed in a subset of melanomas. These two studies add to a wealth of evidence that ERV activity plays a role in cancer development, progression, and treatment, as reviewed by Curty et al. [11] in this issue. Neurodegenerative diseases represent an additional aging-associated context in which activation of ERVs has been implicated in disease onset and progression. In particular, multiple sclerosis was the first neurodegenerative disease for which a connection to HERV-W activity was suggested, with the evidence for HERV-W contributions to MS reviewed by Tarlinton et al. [12].
In summary, this set of papers lays out the state of our knowledge to date on ERV interactions with their host genomes, responses of the host to block ERV activity, and diseases that may involve aberrant de-regulation of ERV activity. Yet, there are still numerous unanswered questions about how ERVs impact, and interact with, their hosts. We anticipate many new and surprising discoveries in this fast-moving field of ERV biology that will likely open up new avenues of research and shed light on how ERVs are linked to health and disease.

Conflicts of Interest:
The authors declare no conflict of interest.