A molecular roadmap of reprogramming somatic cells into iPS cells

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

Research output: Contribution to journalArticle

489 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 (US)
Pages (from-to)1617-1632
Number of pages16
JournalCell
Volume151
Issue number7
DOIs
StatePublished - Dec 21 2012
Externally publishedYes

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Induced Pluripotent Stem Cells
Stem cells
DNA Methylation
Genes
Genome
Refractory materials
Cellular Reprogramming
Cells
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Polo, J. M., Anderssen, E., Walsh, R. M., Schwarz, B. A., Nefzger, C. M., 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

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 journalArticle

Polo, JM, Anderssen, E, Walsh, RM, Schwarz, BA, Nefzger, CM, Lim, SM, Borkent, M, Apostolou, E, Alaei, S, Cloutier, J, Bar-Nur, O, Cheloufi, S, Stadtfeld, M, Figueroa, M, 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
Polo JM, Anderssen E, Walsh RM, Schwarz BA, Nefzger CM, Lim SM et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012 Dec 21;151(7):1617-1632. https://doi.org/10.1016/j.cell.2012.11.039
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. / A molecular roadmap of reprogramming somatic cells into iPS cells. In: Cell. 2012 ; Vol. 151, No. 7. pp. 1617-1632.
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