Letter | Published:

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

Nature Genetics volume 45, pages 325329 (2013) | Download Citation

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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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

Affiliations

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

    • Edward B Chuong
    •  & Julie C Baker
  2. Institute for Reproductive Health and Regenerative Medicine, Departments of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • M A Karim Rumi
    •  & Michael J Soares

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Edward B Chuong or Julie C Baker.

Supplementary information

PDF files

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    Supplementary Text and Figures

    Supplementary Figures 1–5

Excel files

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    Supplementary Table 1

    Putative regulatory TEs in mouse TSCs, H3K9me3

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    Supplementary Table 2

    Putative regulatory TEs in mouse TSCs, H3K27me3

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    Supplementary Table 3

    Putative regulatory TEs in mouse TSCs, H3K4me3/TSS

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    Supplementary Table 4

    Putative regulatory TEs in mouse TSCs, H3K4me1/distal

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    Supplementary Table 5

    Putative regulatory TEs in mouse TSCs, H3K27ac/distal

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    Supplementary Table 6

    Putative regulatory TEs in mouse TSCs, Eomes

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    Supplementary Table 7

    Putative regulatory TEs in mouse TSCs, Cdx2

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    Supplementary Table 8

    Putative regulatory TEs in mouse TSCs, Elf5

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    Supplementary Table 9

    Putative regulatory TEs in rat TSCs, H3K9me3

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    Supplementary Table 10

    Putative regulatory TEs in rat TSCs, H3K27me3

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    Supplementary Table 11

    Putative regulatory TEs in rat TSCs, H3K4me3/TSS

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    Supplementary Table 12

    Putative regulatory TEs in rat TSCs, H3K4me1/distal

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    Supplementary Table 13

    Putative regulatory TEs in rat TSCs, H3K27ac/distal

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DOI

https://doi.org/10.1038/ng.2553