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

Abstract

A fundamental challenge in biology is explaining the origin of novel phenotypic characters such as new cell types; the molecular mechanisms that give rise to novelties are unclear. 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.

High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression

“…We expect that further study of more complex genomes with higher transposon contents, such as mammalian or plant genomes, will uncover even greater numbers of such instances. Additionally, our study focused very specifically on transposons providing promoters, but these elements have been shown to have the potential to also contribute TFBSs, enhancers, silencers, insulators, or microRNA target sites (Bourque et al 2008;Bourque 2009;Lindblad-Toh et al 2011;Lynch et al 2011). Overall, our observations underscore the potential of transposons as a powerful and versatile creative force in regulatory innovation.…”

“…Thus, different fragments derived from the same original element may confer vastly different expression specificities, or even carry out other molecular functions. For instance, different human MER20 insertions can bear, in the same cell type, chromatin profiles that are characteristic of either transcriptional enhancers, repressors, or insulators (Lynch et al 2011). Therefore, even a strict interpretation of the copy-and-paste model does not necessarily imply simple and systematic expression profile correlations between fragments belonging to the same TE family.…”

“…This is quite a striking result, since the detection of such broadly correlated patterns is only possible if a large fraction of gene-driving insertions possess the same specificity. As the analysis of certain transposon sequences has shown, however, a large number of diverse TFBS motifs can often be found throughout the length of the sequence (see, e.g., Lynch et al 2011). Thus, different fragments derived from the same original element may confer vastly different expression specificities, or even carry out other molecular functions.…”

When Competing Viruses Unify: Evolution, Conservation, and Plasticity of Genetic Identities

“…This means that 3.3 gB of human DNA (current size of our genome) was once retrovirus during our evolution. But such LTRs are highly involved in the emergence of new regulatory networks, such as the origin of the placenta (Bièche et al 2003;Chuong et al 2013;Emera and Wagner 2012;Harris 1998;Nakagawa et al 2013) (re-regulating 1500 genes) Lynch et al 2011Lynch et al , 2012 or in the African primates where alteration of 320,000 LTR p53 binding sites occurred onto the p53 cell cycle control network (Wang et al 2007). These primate p53 network changes also relate to (co-operate with) changes in brain specific microRNAs (Le et al 2009), alterations to DNA methylation involved in controlling SINE-derived RNA transcription (Leonova et al 2013), as well as Alu-derived transcription (Zemojtel et al 2009 In proposing the qs-c concept, it was argued that agent diversity (not errors) was essential for the capacity of a collective of RNA agents to function co-operatively (Villarreal and Witzany 2013b).…”

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

“…Interestingly, TEs that were conserved at unusually high levels over hundreds of millions of years were reported to act as enhancers (Bejerano et al 2006;Santangelo et al 2007;Sasaki et al 2008;LindbladToh et al 2011;Lowe and Haussler 2012). Recently, a number of publications proposed that the spreading of copies from active TE classes can lead to rapid rewiring, affecting hundreds of genes whose expression is being altered as a consequence, and is caused by the action of additional transcription factors binding to those enhancers Bourque et al 2008;Feschotte 2008;Xie et al 2010;Lynch et al 2011;Rebollo et al 2012). This might even involve Alu elements in the form of Alu-derived miRNAs or non-miRNAs Hoffman et al 2013;Liang and Yeh 2013;Mandal et al 2013;Spengler et al 2014).…”