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

Abstract

Significance In this study, we found that human endogenous retoriviruses type-H (HERV-Hs) are transiently hyperactivated during reprogramming toward induced pluripotent stem cells (iPSCs) and play important roles in this process. However, when reprogramming is complete and cells acquire full pluripotency, HERV-H activity should decrease to levels comparable with those in embryonic stem cells because failure to resilence this activity leads to the differentiation-defective phenotype in neural lineage. We also found that during reprogramming, reprogramming factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), and Krüppel-like factor 4 (KLF4) (OSK) bind to and activate long-terminal repeats of HERV-Hs. KLF4 possibly precludes Tripartite motif containing 28 and recruits not only OCT3/4 and SOX2, but also E1A binding protein p300 (p300) histone acethyltransferase on HERV-H loci. Therefore, OKSM-induced HERV-H activation constitutes an unanticipated and critical mechanism for iPSC formation.

Present and future challenges of induced pluripotent stem cells

“…Because of that iPSC diversity could be due to the epigenetic dynamics during the process of iPSC generation from cells of somatic origin. This idea is supported by the evidence that some distinct iPSC lines exhibit features of incomplete reprogramming [57]. Many of the reported 'incomplete' human/mouse iPSC lines have characteristics that are similar to ESCs, such as morphology, marker gene expression and basic pluripotency represented in the teratoma formation, while they exhibit particular defects such as poor quality of differentiation, low growth rate, aberrant transcription, DNA methylation, chromatin regulation or chimeric animal contribution in mouse [58 -63].…”

“…However, there have not been many reports that exhibited the link between biological phenotype and molecular marker of human ES/ iPSCs. For example, KLF4, one of the reprogramming factors, was considered to interrupt neurogenesis of iPSCs [57,64]. XIST is also implied as a benchmark to assess human ESC/ iPSC quality.…”

“…In contrast, incomplete reprogramming produced clones with distinguishable properties. A recent study has further shown that approximately 40% of the 3771 human endogenous retroviruses type-H (HERV-Hs) on the human genome are transiently activated during reprogramming [57]. An aberrant increase of HERV-H expression in human ESCs/ iPSCs caused by failure of silencing induces a defective phenotype in the directed differentiation into the neural lineage [57,77].…”

“…A recent study has further shown that approximately 40% of the 3771 human endogenous retroviruses type-H (HERV-Hs) on the human genome are transiently activated during reprogramming [57]. An aberrant increase of HERV-H expression in human ESCs/ iPSCs caused by failure of silencing induces a defective phenotype in the directed differentiation into the neural lineage [57,77]. Therefore, with the exception of incompletely reprogrammed clones, substantially mature iPSCs are thought to be indistinguishable (with regard to gene expression and epigenetic status) from ESCs.…”

Derivation and application of pluripotent stem cells for regenerative medicine

“…Similar to nuclear transfer, some maternal factors, such as TH2A and TH2B (Shinagawa et al, 2014), can promote iPSCs reprogramming. Also, the activity of endogenous retrovirus HERVH was shown to have connection with pluripotency of human iPSCs (Ohnuki et al, 2014). Notably, that the maternal unmethylated Dlk1-Dio3 region would turn methylation during iPSC reprogramming, which may be caused by disorder of c-Myc and/or Gtl2 (Das et al, 2015), is a key reason for loss of capability of tetraploid embryo complementation Stadtfeld et al, 2010).…”