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

Anne Mey,Violaine Tribollet,Sébastien Gounel,Hervé Acloque,Anne-Marie Birot,M Angela Nieto,Jacques Samarut,Sophie Blanc,Emmanuelle Lerat,Damien Curton

doi:10.1186/1742-4690-9-21

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.

Highlights

Long 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
We show here that the Ens-1 LTR is under the control of both Nanog and Gata factors in such a way that may direct the formation of the extraembryonic endoderm when embryonic stem (ES) cells exit pluripotency
A cooperation between distinct DNA motifs controls the activity of the Ens-1 promoter The promoter activity of Ens-1 in the chicken ES cells is supported by a 455 bp sequence (p455) upstream of the transcription initiation site and isolated from the U3 domain of the whole LTR [25]

Summary

Introduction

Long 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. Long terminal repeats (LTR) from endogenous retroviruses (ERV) are remnants of transposable elements disseminated in the genome that contain promoter activity [1] and can control nearby genes in different organisms [2,3,4,5] They represent a source of binding sites for transcription factors [6], and some that are ES cells are isolated from the inner cell mass of very early embryos and can generate all the cells of an organism [9], a unique property called pluripotency that is supported by Oct3/4 [10], Sox2 [11] and Nanog [12] transcription factors. It is not clear what mechanisms guide pluripotent cells toward embryonic or extraembryonic lineages upon the suppression of the controls exerted by Oct3/4 [21] and Nanog [15]

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