Permissive epigenomic states endow reprogramming competence to a broad range of transcriptional regulators

Identifying molecular targets that regulate reprogramming competence of transcription factors in donor cells broadens our understanding of reprogramming process. Here, by a chemical screen targeting major epigenetic pathways in human reprogramming, we discovered that inhibiting specific epigenetic roadblocks allows iPSC generation with almost all OCT factors. Amongst these epigenetic pathways was not only DOT1L-mediated H3K79 methylation but also other modifications catalyzed by LSD1, DNMTs and HDACs, and we found that simultaneous inhibition of these pathways not only dramatically enhances reprogramming competence of most OCT factors but in fact enables to dismantle species-dependent reprograming competence of OCT6, NR5A1, NR5A2, TET1 and GATA3. Harnessing these permissive epigenetic states, we performed an additional screen with 98 transcriptional regulators. Thereby, we identified 25 novel genes that can functionally replace OCT4 in inducing pluripotency. Our findings provide a conceptional framework for understanding how transcription factors elicit reprogramming in dependency of the donor cell epigenome that differs across species. Overall design: Examination of OCT4 and OCT7 binding events in cells undergoing reprogramming.