Endogenous Retroviruses Drive Lineage-Specific Regulatory Evolution across Primate and Rodent Placentae

Abstract

In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal-fetal tolerance. The placenta is highly diverse across mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse late-gestation placentae, we identified hundreds of genes with lineage-specific expression—including dozens that are placentally-enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers and found they highly overlap with specific families of endogenous retroviruses (ERVs), including MER21A, MER41A/B and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41A/B insertions create dozens of lineage-specific Serum Response Factor (SRF) binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Overall, our results demonstrate the prevalence of lineage-specific placental enhancers which are frequently associated with ERV insertions and likely facilitate the lineage-specific evolution of the mammalian placenta.

Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity

“…Together with our previous work in human cells (Chuong et al 2016), our discovery that lineage-specific TEs have been independently co-opted to regulate ISGs in multiple species draws parallels to the finding that ERVs have been repeatedly co-opted to mediate placentation in mammals (Dupressoir et al 2012;Sun et al 2021;Chuong et al 2013;Dunn-Fletcher et al 2018). A growing number of case examples have been discovered where unrelated TEs have been co-opted for convergent functions in multiple species, suggesting that TEs may have a propensity to facilitate the evolution of certain biological processes, particularly those involving genetic conflicts.…”

Regulation of human trophoblast gene expression by endogenous retroviruses

“…A fascinating example of a human placental TE-derived enhancer has also been described, wherein a THE1B ERV regulates the expression of the corticotropin-releasing hormone, affecting gestational length when inserted into the mouse genome (Dunn-Fletcher et al, 2018). More recently, the Macfarlan lab has used epigenomic data to identify a group of putative lineage-specific placental enhancers that are derived from ERVs (Sun et al, 2021). However, as the placenta is a heterogeneous tissue, it remains unclear whether all of these ERVs are active in trophoblast cells, and a genetic demonstration of their regulatory action is lacking.…”

Analysis of Simian Endogenous Retrovirus (SERV) Full-Length Proviruses in Old World Monkey Genomes

“…The large number of SERV proviral integrations, with several hundreds of fixed loci having been detected in the average OWM species, profoundly alter the architecture of the OWM genomes, not only by their presence and coding capacity, but also by recombination of homologous viral sequences, and by the ability of LTRs to function as novel promoters and influence gene expression. The important role of transposable elements in reshaping mammalian development, and especially in ERV-driving lineage-specific evolution of the placenta, has been recognized [ 54 , 55 ]. ERVs that have lost env coding capacity can become “superspreaders”, multiplying disproportionately and taking over a considerable part of the host genome [ 56 , 57 ].…”