Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naive state

Derivation of human naive cells in the ground state of pluripotency provides promising avenues for developmental biology studies and therapeutic manipulations. However, the molecular mechanisms involved in the establishment and maintenance of human naive pluripotency remain poorly understood. Using the human inducible reprogramming system together with the 5iLAF naive induction strategy, integrative analysis of transcriptional and epigenetic dynamics across the transition from human fibroblasts to naive iPSCs revealed ordered waves of gene network activation sharing signatures with those found during embryonic development from late embryogenesis to pre-implantation stages. More importantly, Transcriptional analysis showed a significant transient reactivation of transcripts with 8-cell-stage-like characteristics in the late stage of reprogramming, suggesting transient activation of gene network with human zygotic genome activation (ZGA)-like signatures during the establishment of naive pluripotency. Together, Dissecting the naIve reprogramming dynamics by integrative analysis improves the understanding of the molecular features involved in the generation of naive pluripotency directly from somatic cells.