A molecular roadmap of reprogramming somatic cells into iPS cells

Jose Maria Polo, Endre Anderssen, Ryan M Walsh, Benjamin A Schwarz, Christian Nefzger, Sue Mei Lim, Marti Borkent, Effie Apostolou, Sara Alaei Shehni, Jennifer Cloutier, Ori Bar-Nur, Sihem Cheloufi, Matthias Stadtfeld, Maria E Figueroa, Daisy Robinton, Sridaran Natesan, Ari Melnick, Jinfang Zhu, Sridhar Ramaswamy, Konrad Hochedlinger

Research output: Contribution to journalArticleResearchpeer-review

598 Citations (Scopus)


Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, whereas changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming.
Original languageEnglish
Pages (from-to)1617 - 1632
Number of pages16
Issue number7
Publication statusPublished - 2012

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