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.