Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency

Abstract

Endogenous retroelements (EREs) account for about half of the mouse or human genome, and their potential as insertional mutagens and transcriptional perturbators is suppressed by early embryonic epigenetic silencing. Here, we asked how ERE control is maintained during the generation of induced pluripotent stem cells (iPSCs), as this procedure involves profound epigenetic remodeling. We found that all EREs tested were markedly up-regulated during the reprogramming of either mouse embryonic fibroblasts, human CD34(+) cells, or human primary hepatocytes. At the iPSC stage, EREs of some classes were repressed, whereas others remained highly expressed, yielding a pattern somewhat reminiscent of that recorded in embryonic stem cells. However, variability persisted between individual iPSC clones in the control of specific ERE integrants. Both during reprogramming and in iPS cells, the up-regulation of specific EREs significantly impacted on the transcription of nearby cellular genes. While transcription triggered by specific ERE integrants at highly precise developmental stages may be an essential step toward obtaining pluripotent cells, the broad and unspecific unleashing of the repetitive genome observed here may contribute to the inefficiency of the reprogramming process and to the phenotypic heterogeneity of iPSCs.

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

“…Finally, RNA-Seq expression of HEMO was analyzed in the reprogramming experiments of differentiated somatic cells into iPSCs described in ref. 32, and hits reported in Fig. 7A, Right highlight the specific reprogramming of the HEMO gene-not observed with env-W and env-FRD-which parallels the expected profile of expression of the OCT4/ POU5F1 transcription factor.…”

“…To get insight into the possible involvement of HEMO in embryonic development, we further analyzed by data mining a series of human RNA sequencing (RNA-Seq) experiments deposited at the Sequence Read Archive National Center for Biotechnology Information platform corresponding to different stages of development (29)(30)(31)(32). Extraction of the expression profiles of a set of human genes was performed, and the results are illustrated in Fig.…”

Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

“…Another study showed that a small portion of mouse ESCs and iPSCs express ERV-L retroviruses and possess the ability to differentiate not only into embryonic lineages but also into extraembryonic cells (30). Recently, Friedli et al showed that aberrant activation of intracisternal A particle, a member of ERV-K, occurred during reprogramming of mouse embryonic fibroblasts toward iPSCs, as well as HERV-H behavior in a human case, which may suggest the importance of ERV activity in reprogramming beyond species (31). An important future task will involve examining the roles of speciesspecific ERVs in reprogramming and pluripotency.…”

A developmental framework for induced pluripotency

“…Additionally, a recent study has shown that ∼40% of 3771 human endogenous retroviruses type-H (HERV-Hs) transcripts, which are detected in both human pluripotent stem cells and mesendodermal cells, are transiently hyper-activated during reprogramming (Friedli et al, 2014;Lu et al, 2014;Ohnuki et al, 2014;Wang et al, 2014). Furthermore, human ESCs and iPSCs expressing aberrantly high levels of HERV-H transcripts show defective directed differentiation down the neural lineage (Koyanagi-Aoi et al, 2013; Ohnuki et al, 2014).…”