The endogenous retrovirus ENS-1 provides active binding sites for transcription factors in embryonic stem cells that specify extra embryonic tissue

Abstract

BackgroundLong terminal repeats (LTR) from endogenous retroviruses (ERV) are source of binding sites for transcription factors which affect the host regulatory networks in different cell types, including pluripotent cells. The embryonic epiblast is made of pluripotent cells that are subjected to opposite transcriptional regulatory networks to give rise to distinct embryonic and extraembryonic lineages. To assess the transcriptional contribution of ERV to early developmental processes, we have characterized in vitro and in vivo the regulation of ENS-1, a host adopted and developmentally regulated ERV that is expressed in chick embryonic stem cells.ResultsWe show that Ens-1 LTR activity is controlled by two transcriptional pathways that drive pluripotent cells to alternative developmental fates. Indeed, both Nanog that maintains pluripotency and Gata4 that induces differentiation toward extraembryonic endoderm independently activate the LTR. Ets coactivators are required to support Gata factors' activity thus preventing inappropriate activation before epigenetic silencing occurs during differentiation. Consistent with their expression patterns during chick embryonic development, Gata4, Nanog and Ets1 are recruited on the LTR in embryonic stem cells; in the epiblast the complementary expression of Nanog and Gata/Ets correlates with the Ens-1 gene expression pattern; and Ens-1 transcripts are also detected in the hypoblast, an extraembryonic tissue expressing Gata4 and Ets2, but not Nanog. Accordingly, over expression of Gata4 in embryos induces an ectopic expression of Ens-1.ConclusionOur results show that Ens-1 LTR have co-opted conditions required for the emergence of extraembryonic tissues from pluripotent epiblasts cells. By providing pluripotent cells with intact binding sites for Gata, Nanog, or both, Ens-1 LTR may promote distinct transcriptional networks in embryonic stem cells subpopulations and prime the separation between embryonic and extraembryonic fates.

Subcellular Localization of ENS-1/ERNI in Chick Embryonic Stem Cells

“…In a previous report we have shown that the promoter of Ens-1 is repressed while the expression of Sox2 is induced when CES differentiate [8]. These results are in agreement with the idea that differentiation of CES in vitro may mimic the release of the repression mediated by the dimer ENS-1/HP1γ on the promoter of Sox2 before the emergence of the neural plate.…”

“…Silencing of the gene occurs later, as final differentiation is achieved [8], [9]. In the epiblast, this expression pattern is managed by the pluripotency transcription factor Nanog and by a combination of Gata and Ets transcription factors that are expressed in the epiblast, in the hypoblast and in the prospective neural plate [8].…”

TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells

“…Whether some ERV-derived enhancers serve as docking sites for this repressor system in these adult tissues warrants exploration. There is evidence that some ERV sequences function as authentic regulators, including enhancers, in certain cells, not only during development but also in adult tissues (Pi et al 2004;Bourque et al 2008;Kunarso et al 2010;Teng et al 2011;Mey et al 2012;Schmidt et al 2012). Our data indicate that these rare coopted elements represent only exceptions within a large group, most members of which are repressed through TRIM28.…”

“…Accordingly, it is noteworthy that the long terminal repeats (LTRs) of ERVs harbor binding sites for numerous transcription factors, as expected from the needs of their own replication. Furthermore, rare ERV-contained sequences have been found to function as cisacting regulatory elements during mouse, human, and chick development through their recruitment of proteins such as POU5F1 (also called OCT4), GATA4, and CTCF (Bourque et al 2008;Kunarso et al 2010;Mey et al 2012;Schmidt et al 2012). ERVs and cellular genes can additionally be coordinately controlled in ES cells Macfarlan et al 2011Macfarlan et al , 2012.…”

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

“…ERV-contained sequences regulate vertebrate development (Wang et al 2007;Bourque et al 2008;Kunarso et al 2010;Mey et al 2012;Schmidt et al 2012) and contributed, for instance, to the evolutionary diversification of the placenta (Chuong et al 2013). Moreover, ERVs can serve as tissuespecific promoters or enhancers for cellular genes, and control of some ERV-cellular gene pairs is coordinated notably in ES cells (Buzdin et al 2006;Karimi et al 2011;Macfarlan et al 2011Macfarlan et al , 2012Rebollo et al 2011).…”