The connection between ERVs and placentas is already well established.
Without a shadow of a doubt, the ability of mammals to generate placentas was, in part, accomplished by domesticating an endogenous retroviral env protein. In humans, we call this protein syncytin, or ERVWE1.
This new paper in Nature Genetics takes the ERV-Placenta connection a step further:
Even though all mammals have placentas, mammalian placentas are different, even between species we would think should be very similar, like the subjects of this paper, mice and rats. Between mice and rats, the building blocks of a placenta, the genes, are related, and yet the mature placentas are distinct.
You might have run into this situation before– You know how humans and chimpanzees and bonobos share most of the same genes… and yet humans and chimpanzees and bonobos are all distinct species? The ‘trick’ is the regulation of the ‘same’ genes. More of Gene A. Less of Gene B. Gene C doesnt turn on at all. Gene D is expressed at the same rate, but earlier. Gene E later. Different species are different recipes using the same ingredients.
And it appears as if ERVs are helping write the recipes in mouse and rat placentas.
These researchers started by mapping the epigenetic landscape of the mouse and rat embryonic cells that start making mouse and rat placentas. And by ‘mapped the epigenetic landscape’ I dont mean they measured how happy the mouse stem cells were, or fed the rat cells all organic non-GMO media. I mean they mapped the location of epigenetic markers that indicate actively transcribed DNA, and silenced DNA. Please note the lack of magic:
…promoters (trimethylation of histone H3 at lysine 4 (H3K4me3)), enhancers (H3K4me1 and H3K27ac) and repressed regions (trimethylation at histone H3 lysine 27 (H3K27me3) and trimethylation at histone H3 lysine 9 (H3K9me3))…
Even though the genes to build placentas in mice and rats are relatively similar, the epigenetic profile of the embryonic cells that turn into the placenta were totally different between mice and rats:
We predicted 9,460 mouse and 7,932 rat TSC promoters on the basis of H3K4me3 enrichment over gene transcriptional start sites (TSSs), which were associated with expressed genes (Fig. 1a,b). We predicted 52,476 mouse and 41,142 rat TSC enhancers on the basis of distal enrichment of H3K4me1 (>5 kb from a gene TSS) and 25,736 mouse and 4,471 rat regions of distal H3K27ac enrichment. These predicted enhancers were significantly enriched near genes with annotated placental function (P = 1 × 10−51, binomial test; Supplementary Fig. 1).
We found that, although the majority of promoter regions were conserved between mouse and rat, both enhancer and repressed regions were predominantly species specific.
Whats more, is that of the 80% of enhancers that were mouse-specific or rat-specific were next to transposable elements. What kind of TE? ERVs. What kind of ERVs? Species specific ERVs.
There are many, many ERVs in mouse/rat genomes. The only ones they would be interested would be the ones near the 52,476 mouse and 41,142 rat TSC enhancers… but… um… that doesnt entirely help narrow things down.
So they focused on a mouse-specific ERV family they found hanging out with their epigenetic enhancer regions, RLTR13D5. They poked around, trying to find potential enhancer sequences of DNA hidden in the carcass of dead ERVs. And they found them. In the ERVs hanging out with transcription factors that have previously been associated with placental development– Eomes, Cdx2 and Elf5.
But that doesnt mean that the ERV carcasses are actually used as enhancers. Just because those three proteins can bind to the ERV carcass, it doesnt mean they do.
Sometimes, they do:
Overall, we found that 35% (336) of all genomic regions triply bound by Eomes, Cdx2 and Elf5 were derived directly from the mouse-specific RLTR13 ERV superfamily, demonstrating their central role in substantially reshaping the TSC core regulatory network.
Okay, well, just because they do bind to ERV enhancers, that doesnt mean they actually do anything in vivo.
Sometimes, they do. They found some genes downstream of putative species specific ERV enhancer regions, and used a reporter system to determine if that really resulted in species specific expression of their reporter (could they make rat cells, which dont have RLTR13D5, use RLTR13D5 in an artificial expression system). It worked.
Overall, these results show that RLTR13D5 is capable of driving gene expression in placental cells and provide strong evidence that RLTR13-derived enhancers have facilitated the evolution of mouse-specific gene expression patterns in TSCs.
As if this wasnt enough, these folks looked in non-placental tissue for similar patterns… and didnt really see it. The putative ERV carcasses involved were old (read: not species specific).
We have ERVs to thank for our ability to make placentas. Go figure :-/
We suggest that species-specific ERVs contribute to the rapid divergence of the placental gene regulatory network.