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Review
. 2015 Mar;35(5):770-7.
doi: 10.1128/MCB.01293-14. Epub 2014 Dec 29.

Retroviral transcriptional regulation and embryonic stem cells: war and peace

Sharon Schlesinger  1 , Stephen P Goff  2
Affiliations
Review

Retroviral transcriptional regulation and embryonic stem cells: war and peace

Sharon Schlesinger et al. Mol Cell Biol. 2015 Mar.

Abstract

Retroviruses have evolved complex transcriptional enhancers and promoters that allow their replication in a wide range of tissue and cell types. Embryonic stem (ES) cells, however, characteristically suppress transcription of proviruses formed after infection by exogenous retroviruses and also of most members of the vast array of endogenous retroviruses in the genome. These cells have unusual profiles of transcribed genes and are poised to make rapid changes in those profiles upon induction of differentiation. Many of the transcription factors in ES cells control both host and retroviral genes coordinately, such that retroviral expression patterns can serve as markers of ES cell pluripotency. This overlap is not coincidental; retrovirus-derived regulatory sequences are often used to control cellular genes important for pluripotency. These sequences specify the temporal control and perhaps "noisy" control of cellular genes that direct proper cell gene expression in primitive cells and their differentiating progeny. The evidence suggests that the viral elements have been domesticated for host needs, reflecting the wide-ranging exploitation of any and all available DNA sequences in assembling regulatory networks.

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Figures

FIG 1
FIG 1
Transcriptional regulation of the integrated provirus in embryos and embryonic cells. Trim28 binding to the DNA binding proteins ZFP809 (14) and YY1 (17), as well as to EBP1 (21) and HP1 (20), results in epigenetic silencing of the newly integrated or endogenous provirus elements. The silencing is mediated by Trim28 recruitment of many factors involved in transcriptional silencing and heterochromatin formation, including the histone methyltransferases ESET (22) and G9a (34) and the NuRD histone deacetylase complex (92). These histone modifiers are responsible for the trimethylation of H3K9 (H3K9Me3), H4K20 (H4K20Me3) (22), and H3K27 (H3K27me3) (24) (red and pink circles) histone tails as well as for subsequent DNA methylation (93). NCR, noncoding region.
FIG 2
FIG 2
Examples of domestication of ERV sequences by mouse and human embryonic cells. (A) MERV-L elements and their remnant “solo” long terminal repeats (LTRs) have been coopted to participate in gene regulatory networks by serving as primary or alternative promoters of nearby genes (31). A subset of mouse embryonic stem cells expresses MERV-L LTR-driven chimeric transcripts, which correlates with increased potency (46). (B) HERV-H interacts with Oct4 to promote the enhancer activities of LTR7 and nearby regions and to drive the expression of neighboring lncRNAs and protein-coding genes essential to hES cell identity (59, 61, 63). (C) ERV1 elements in the human and mouse genomes carry transcription factor-binding sites for Oct4 and Nanog, which can regulate genes that form the pluripotency network near insertion sites, leading to novel regulatory patterns in evolving mammals (9, 52).
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