Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Abstract

Transposable elements (TEs) are known to provide DNA for host regulatory functions, but the mechanisms underlying the transformation of TEs into cis-regulatory elements are unclear. In humans two TEs-MER20 and MER39-contribute the enhancer/ promoter for decidual prolactin (dPRL), which is dramatically induced during pregnancy. We show that evolution of the strong human dPRL promoter was a multistep process that took millions of years. First, MER39 inserted near MER20 in the primate/rodent ancestor, and then there were two phases of activity enhancement in primates. Through the mapping of causal nucleotide substitutions, we demonstrate that strong promoter activity in apes involves epistasis between transcription factor binding sites (TFBSs) ancestral to MER39 and derived sites. We propose a mode of molecular evolution that describes the process by which MER20/MER39 was transformed into a strong promoter, called "epistatic capture." Epistatic capture is the stabilization of a TFBS that is ancestral but variable in outgroup lineages, and is fixed in the ingroup because of epistatic interactions with derived TFBSs. Finally, we note that evolution of human promoter activity coincides with the emergence of a unique reproductive character in apes, highly invasive placentation. Because prolactin communicates with immune cells during pregnancy, which regulate fetal invasion into maternal tissues, we speculate that ape dPRL promoter activity evolved in response to increased invasiveness of ape fetal tissue.cis-regulatory evolution | human evolution | human pregnancy I n the pursuit to understand mechanisms underlying the evolution of gene regulation, it has become increasingly clear that transposable elements play a critical role in regulatory evolution by providing novel genetic elements, including new introns, promoters, enhancers, and insulators (1). In addition to individual examples showing that transposable elements (TEs) are associated with host regulatory function, computational work shows that TEs intersect with many promoter regions (2) and are overrepresented in predicted regulatory regions [(3, 4); see review by Feschotte (1)]. Many questions remain unanswered. How frequently are TEs actually co-opted for regulatory function? What is the adaptive significance of these events? Are TEs used by the host genome immediately upon insertion or do they require extensive sequence evolution before acquiring a biological role? What are the molecular changes that transform a transposable element into a cisregulatory element?In this paper we address the latter two questions posed above by investigating evolution of the decidual prolactin promoter in primates. In a recent paper we showed that the prolactin gene was independently recruited into uterine expression in primates, mice, and elephants by the co-option of different transposable elements, highlighting the frequency at which TEs can be recruited and their importance in gene regulatory innovation (5). Here we trace the evolutionary history and function of transposabl...

The evolution of viviparity: molecular and genomic data from squamate reptiles advance understanding of live birth in amniotes

“…We also have yet to identify the elements regulating viviparity-associated gene expression; more genomic information will permit evaluation of potential gene expression promoters and the influence of transposable elements on gene expression (e.g. Emera & Wagner (2012) and Jacques et al (2013)). …”

Comparative validation of the D. melanogaster modENCODE transcriptome annotation

“…A classic example is the expressed pseudogene, which can arise by gene duplication followed by degeneration of one redundant copy by random accumulation of mutations (Balakirev and Ayala 2003;Zheng et al 2007). Functionless transcripts might also arise from transposon promoters (Emera and Wagner 2012;Hancks and Kazazian 2012). It is also reasonable to assume that transcriptional errors occur at a nonzero rate.…”

Evolution of mammalian pregnancy and the origin of the decidual stromal cell

“…In the case of decidual cells, target gene recruitment is, at least in part, mediated through the evolution of alternative promoters and cell type specific enhancers from transposable elements. This was first discovered for the decidual promoter of PRL (Emera et al, 2011a, Emera and Wagner, 2012, Gerlo et al, 2006. The decidual promoter consists of DNA from two transposable elements, MER20 and MER39 (Gerlo et al, 2006).…”

“…The expression of decidual PRL (dPRL) is regulated by an alternative promoter about 6 kb upstream of the first coding exon (Berwaer et al, 1994, Gellersen et al, 1994 that is derived from two transposable elements (Emera et al, 2011a, Emera and Wagner, 2012, Gerlo et al, 2006. A number of transcription factors have been identified that participate in the regulation of dPRL.…”