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Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals


A fundamental challenge in biology is explaining the origin of novel phenotypic characters such as new cell types1,2,3,4; the molecular mechanisms that give rise to novelties are unclear5,6,7. We explored the gene regulatory landscape of mammalian endometrial cells using comparative RNA-Seq and found that 1,532 genes were recruited into endometrial expression in placental mammals, indicating that the evolution of pregnancy was associated with a large-scale rewiring of the gene regulatory network. About 13% of recruited genes are within 200 kb of a Eutherian-specific transposable element (MER20). These transposons have the epigenetic signatures of enhancers, insulators and repressors, directly bind transcription factors essential for pregnancy and coordinately regulate gene expression in response to progesterone and cAMP. We conclude that the transposable element, MER20, contributed to the origin of a novel gene regulatory network dedicated to pregnancy in placental mammals, particularly by recruiting the cAMP signaling pathway into endometrial stromal cells.

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Figure 1: Evolution of the endometrial stromal cell transcriptome in Therian mammals.
Figure 2: MER20s are over-represented near progesterone/cAMP-responsive endometrial genes and have genomic and epigenetic signatures of regulatory elements.
Figure 3: MER20s have binding sites for numerous transcription factors, cofactors and insulator proteins and evolve under functional constraints.
Figure 4: MER20s are bound by transcription factors and cofactors important for decidualization and pregnancy.
Figure 5: MER20 reporter constructs regulate luciferase expression.
Figure 6: MER20s are candidate insulator elements.

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The authors would like to thank A. Pyle and the three anonymous reviewers for comments on an earlier version of this manuscript. We would also like to thank R.W. Truman (National Hansen's Disease Program/US National Institutes of Allergy and Infectious Diseases IAA-2646) and K. Smith for the generous gifts of pregnant armadillo and opossum uterus and R. Bjornson and N. Carriero for assistance with RNA-Seq read mapping. This work was funded by a grant from the John Templeton Foundation, no. 12793, Genetics and the Origin of Organismal Complexity; results presented here do not necessarily reflect the views of the John Templeton Foundation. The funders had no role in study design, data collection and analysis, decision to publish or manuscript preparation.

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Authors and Affiliations



V.J.L. and G.P.W. designed experiments and wrote the manuscript. V.J.L. and G.M. performed experiments and analyzed data, and R.D.L. designed and performed bioinformatics analyses.

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Correspondence to Vincent J Lynch.

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The authors declare no competing financial interests.

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Lynch, V., Leclerc, R., May, G. et al. Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat Genet 43, 1154–1159 (2011).

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