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

493 Citations (Scopus)

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 languageEnglish
Pages (from-to)1617 - 1632
Number of pages16
JournalCell
Volume151
Issue number7
DOIs
Publication statusPublished - 2012

Cite this

Polo, J. M., Anderssen, E., Walsh, R. M., Schwarz, B. A., Nefzger, C., Lim, S. M., ... Hochedlinger, K. (2012). A molecular roadmap of reprogramming somatic cells into iPS cells. Cell, 151(7), 1617 - 1632. https://doi.org/10.1016/j.cell.2012.11.039
Polo, Jose Maria ; Anderssen, Endre ; Walsh, Ryan M ; Schwarz, Benjamin A ; Nefzger, Christian ; Lim, Sue Mei ; Borkent, Marti ; Apostolou, Effie ; Alaei Shehni, Sara ; Cloutier, Jennifer ; Bar-Nur, Ori ; Cheloufi, Sihem ; Stadtfeld, Matthias ; Figueroa, Maria E ; Robinton, Daisy ; Natesan, Sridaran ; Melnick, Ari ; Zhu, Jinfang ; Ramaswamy, Sridhar ; Hochedlinger, Konrad. / A molecular roadmap of reprogramming somatic cells into iPS cells. In: Cell. 2012 ; Vol. 151, No. 7. pp. 1617 - 1632.
@article{12c445c3a1284f6d87622281200c577f,
title = "A molecular roadmap of reprogramming somatic cells into iPS cells",
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.",
author = "Polo, {Jose Maria} and Endre Anderssen and Walsh, {Ryan M} and Schwarz, {Benjamin A} and Christian Nefzger and Lim, {Sue Mei} and Marti Borkent and Effie Apostolou and {Alaei Shehni}, Sara and Jennifer Cloutier and Ori Bar-Nur and Sihem Cheloufi and Matthias Stadtfeld and Figueroa, {Maria E} and Daisy Robinton and Sridaran Natesan and Ari Melnick and Jinfang Zhu and Sridhar Ramaswamy and Konrad Hochedlinger",
year = "2012",
doi = "10.1016/j.cell.2012.11.039",
language = "English",
volume = "151",
pages = "1617 -- 1632",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier",
number = "7",

}

Polo, JM, Anderssen, E, Walsh, RM, Schwarz, BA, Nefzger, C, Lim, SM, Borkent, M, Apostolou, E, Alaei Shehni, S, Cloutier, J, Bar-Nur, O, Cheloufi, S, Stadtfeld, M, Figueroa, ME, Robinton, D, Natesan, S, Melnick, A, Zhu, J, Ramaswamy, S & Hochedlinger, K 2012, 'A molecular roadmap of reprogramming somatic cells into iPS cells', Cell, vol. 151, no. 7, pp. 1617 - 1632. https://doi.org/10.1016/j.cell.2012.11.039

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

In: Cell, Vol. 151, No. 7, 2012, p. 1617 - 1632.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A molecular roadmap of reprogramming somatic cells into iPS cells

AU - Polo, Jose Maria

AU - Anderssen, Endre

AU - Walsh, Ryan M

AU - Schwarz, Benjamin A

AU - Nefzger, Christian

AU - Lim, Sue Mei

AU - Borkent, Marti

AU - Apostolou, Effie

AU - Alaei Shehni, Sara

AU - Cloutier, Jennifer

AU - Bar-Nur, Ori

AU - Cheloufi, Sihem

AU - Stadtfeld, Matthias

AU - Figueroa, Maria E

AU - Robinton, Daisy

AU - Natesan, Sridaran

AU - Melnick, Ari

AU - Zhu, Jinfang

AU - Ramaswamy, Sridhar

AU - Hochedlinger, Konrad

PY - 2012

Y1 - 2012

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.ncbi.nlm.nih.gov/pubmed/23260147?dopt=Citation

U2 - 10.1016/j.cell.2012.11.039

DO - 10.1016/j.cell.2012.11.039

M3 - Article

VL - 151

SP - 1617

EP - 1632

JO - Cell

JF - Cell

SN - 0092-8674

IS - 7

ER -