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Endogenous retroviruses function as species-specific enhancer elements in the placenta

Nature Genetics volume 45, pages 325–329 (2013)Cite this article

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Abstract

The mammalian placenta is remarkably distinct between species, suggesting a history of rapid evolutionary diversification1. To gain insight into the molecular drivers of placental evolution, we compared biochemically predicted enhancers in mouse and rat trophoblast stem cells (TSCs) and found that species-specific enhancers are highly enriched for endogenous retroviruses (ERVs) on a genome-wide level. One of these ERV families, RLTR13D5, contributes hundreds of mouse-specific histone H3 lysine 4 monomethylation (H3K4me1)- and histone H3 lysine 27 acetylation (H3K27ac)-defined enhancers that functionally bind Cdx2, Eomes and Elf5—core factors that define the TSC regulatory network. Furthermore, we show that RLTR13D5 is capable of driving gene expression in rat placental cells. Analysis in other tissues shows that species-specific ERV enhancer activity is generally restricted to hypomethylated tissues, suggesting that tissues permissive for ERV activity gain access to an otherwise silenced source of regulatory variation. Overall, our results implicate ERV enhancer co-option as a mechanism underlying the extensive evolutionary diversification of placental development.

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Figure 1: The epigenetic landscape of mouse TSCs determined using histone ChIP-seq.
Figure 2: Comparison of mouse and rat shows overabundance of species-specific ERVs in enhancer regions.
Figure 3: The mouse-specific ERV RLTR13D5 is highly enriched within placental enhancers.
Figure 4: Core TSC transcription factors bind RLTR13D5 copies.
Figure 5: RLTR13D5 functions to drive trophoblast expression.
Figure 6: RLTR13D5 enhancer cooption is placenta specific, and species-specific ERV enhancer activity is restricted to TSCs, ESCs and testis.

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Acknowledgements

The authors wish to thank G. Barsh for helpful comments, the laboratory of A. Sidow for assistance with sequencing and J. Rossant (Hospital for Sick Children) for contribution of mouse TSCs. This work was supported by the Stanford Genome Training Grant (E.B.C.; T32 HG000044), a National Science Foundation Graduate Research Fellowship (E.B.C.; 2008052909), the Stanford Bio-X program (J.C.B.) and the Burroughs Welcome Prematurity Initiative (J.C.B.; 1008847).

Author information

Authors and Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Edward B Chuong & Julie C Baker

  2. Departments of Pathology & Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA

    M A Karim Rumi & Michael J Soares

Authors
  1. Edward B Chuong
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  2. M A Karim Rumi
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  3. Michael J Soares
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  4. Julie C Baker
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Contributions

E.B.C. and J.C.B. conceived and designed the study and wrote the manuscript. E.B.C. designed and performed RNA-seq and ChIP-seq experiments and analyzed the data. M.A.K.R. and M.J.S. provided rat samples. M.A.K.R. performed luciferase assays.

Corresponding authors

Correspondence to Edward B Chuong or Julie C Baker.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 4086 kb)

Supplementary Table 1

Putative regulatory TEs in mouse TSCs, H3K9me3 (XLS 141 kb)

Supplementary Table 2

Putative regulatory TEs in mouse TSCs, H3K27me3 (XLS 116 kb)

Supplementary Table 3

Putative regulatory TEs in mouse TSCs, H3K4me3/TSS (XLS 98 kb)

Supplementary Table 4

Putative regulatory TEs in mouse TSCs, H3K4me1/distal (XLS 145 kb)

Supplementary Table 5

Putative regulatory TEs in mouse TSCs, H3K27ac/distal (XLS 134 kb)

Supplementary Table 6

Putative regulatory TEs in mouse TSCs, Eomes (XLS 115 kb)

Supplementary Table 7

Putative regulatory TEs in mouse TSCs, Cdx2 (XLS 93 kb)

Supplementary Table 8

Putative regulatory TEs in mouse TSCs, Elf5 (XLS 119 kb)

Supplementary Table 9

Putative regulatory TEs in rat TSCs, H3K9me3 (XLS 101 kb)

Supplementary Table 10

Putative regulatory TEs in rat TSCs, H3K27me3 (XLS 71 kb)

Supplementary Table 11

Putative regulatory TEs in rat TSCs, H3K4me3/TSS (XLS 87 kb)

Supplementary Table 12

Putative regulatory TEs in rat TSCs, H3K4me1/distal (XLS 125 kb)

Supplementary Table 13

Putative regulatory TEs in rat TSCs, H3K27ac/distal (XLS 86 kb)

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Chuong, E., Rumi, M., Soares, M. et al. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat Genet 45, 325–329 (2013). https://doi.org/10.1038/ng.2553

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