TitleA molecular roadmap of reprogramming somatic cells into iPS cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsPolo, Jose M., Anderssen Endre, Walsh Ryan M., Schwarz Benjamin A., Nefzger Christian M., Lim Sue Mei, Borkent Marti, Apostolou Effie, Alaei Sara, Cloutier Jennifer, Bar-Nur Ori, Cheloufi Sihem, Stadtfeld Matthias, Figueroa Maria Eugenia, Robinton Daisy, Natesan Sridaran, Melnick Ari, Zhu Jinfang, Ramaswamy Sridhar, and Hochedlinger Konrad
Date Published2012 Dec 21
KeywordsAnimals, Cellular Reprogramming, Cytological Techniques, Genome-Wide Association Study, Humans, Induced Pluripotent Stem Cells, Kruppel-Like Factor 4, Mice, Transcription Factors

<p>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.</p>

Alternate JournalCell
PubMed ID23260147
PubMed Central IDPMC3608203
Grant ListDP2OD003266 / OD / NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
DP2 OD003266 / OD / NIH HHS / United States
ZIA AI001169-01 / ImNIH / Intramural NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
R01 HD058013 / HD / NICHD NIH HHS / United States
R01HD058013 / HD / NICHD NIH HHS / United States
P01 GM099117 / GM / NIGMS NIH HHS / United States