Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells

Abstract

Summary Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, which comprise nearly 8% of the human genome1. The most recently acquired human ERV is HERV-K (HML-2), which repeatedly infected the primate lineage both before and after the divergence of humans and chimpanzees2,3. Unlike most other human ERVs, HERV-K retained multiple copies of intact open reading frames (ORFs) encoding retroviral proteins4. However, HERV-K is transcriptionally silenced by the host with exception of certain pathological contexts, such as germ cell tumors, melanoma, or HIV infection5–7. Here we demonstrate that DNA hypomethylation at LTR elements representing the most recent genomic integrations, together with transactivation by OCT4, synergistically facilitate HERV-K expression. Consequently, HERV-K is transcribed during normal human embryogenesis beginning with embryonic genome activation (EGA) at the 8-cell stage, continuing through the emergence of epiblast cells in pre-implantation blastocysts, and ceasing during hESC derivation from blastocyst outgrowths. Remarkably, HERV-K viral-like particles and Gag proteins are detected in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, HERV-K accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERV-K can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, arguing that complex interactions between retroviral proteins and host factors can fine-tune regulatory properties of early human development.

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…Indeed, ERVs can be targeted as tumor-associated antigens on melanoma cells (Cooper et al, 2015). In contrast, as in our present data, and those of others (Maksakova et al, 2008), in some cancers, individual ERVs can maintain full or partial promoter DNA methylation and low expression and DNMTis can induce ERV demethylation and viral defense signaling in human embryonic stem cells (Grow et al, 2015).…”

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

“…De novo heritable L1 retrotransposition is a component of the ongoing evolutionary interplay between retroelements and mammalian genomes, the importance of which is exemplified by recent studies demonstrating the exaptation of LTR retrotransposon sequences and protein products for pluripotency maintenance and embryonic development (Wang et al 2014;Grow et al 2015). Furthermore, recent publications have implicated somatic retrotransposition in the brain as a feature of both normal neurobiology and neurological diseases (Muotri et al 2005(Muotri et al , 2010Coufal et al 2009Coufal et al , 2011Baillie et al 2011;Evrony et al 2012Evrony et al , 2015Bundo et al 2014;Upton et al 2015;Erwin et al 2016).…”

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

“…An effect of HEMO in development should also be considered, taking into consideration that its expression is observed as early as at the eight-cell stage and persists at all of the subsequent embryonic stages. Of note, other ERVs-including HERV-H and HERV-K-have related profiles of expression, and abundant HERV-H RNA was recently shown to be a marker of cell "stemness" in humans and possibly play a role-via transcriptional effects and/or specific ERV-driven transcripts-in the maintenance of pluripotency in human stem cells (45)(46)(47)(48)(49) (reviewed in refs. [50][51][52].…”