Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 1617-1632 |
| Number of pages | 16 |
| Journal | Cell |
| Volume | 151 |
| Issue number | 7 |
| DOIs | |
| State | Published - Dec 21 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
A molecular roadmap of reprogramming somatic cells into iPS cells. / Polo, 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; Robinton, Daisy; Natesan, Sridaran; Melnick, Ari; Zhu, Jinfang; Ramaswamy, Sridhar; Hochedlinger, Konrad.
In: Cell, Vol. 151, No. 7, 21.12.2012, p. 1617-1632.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A molecular roadmap of reprogramming somatic cells into iPS cells
AU - Polo, Jose M.
AU - Anderssen, Endre
AU - Walsh, Ryan M.
AU - Schwarz, Benjamin A.
AU - Nefzger, Christian M.
AU - Lim, Sue Mei
AU - Borkent, Marti
AU - Apostolou, Effie
AU - Alaei, Sara
AU - Cloutier, Jennifer
AU - Bar-Nur, Ori
AU - Cheloufi, Sihem
AU - Stadtfeld, Matthias
AU - Figueroa, Maria
AU - Robinton, Daisy
AU - Natesan, Sridaran
AU - Melnick, Ari
AU - Zhu, Jinfang
AU - Ramaswamy, Sridhar
AU - Hochedlinger, Konrad
PY - 2012/12/21
Y1 - 2012/12/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871586080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871586080&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.11.039
DO - 10.1016/j.cell.2012.11.039
M3 - Article
C2 - 23260147
AN - SCOPUS:84871586080
VL - 151
SP - 1617
EP - 1632
JO - Cell
JF - Cell
SN - 0092-8674
IS - 7
ER -