Prospective Isolation of Poised iPSC Intermediates Reveals Principles of 
Cellular Reprogramming

Schwarz, Benjamin A.; Cetinbas, Murat; Clement, Kendell; Walsh, Ryan M.; Cheloufi, Sihem; Gu, Hongcang; Langkabel, Jan; Kamiya, Akihide; Schorle, Hubert; Meissner, Alexander; Sadreyev, Ruslan I.; Hochedlinger, Konrad

doi:10.1016/j.stem.2018.06.013

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Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

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Meissner, Alexander
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;
Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA;
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;

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Citation

Schwarz, B. A., Cetinbas, M., Clement, K., Walsh, R. M., Cheloufi, S., Gu, H., et al. (2018). Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming. Cell Stem Cell, 23(2): e5, pp. 289-305. doi:10.1016/j.stem.2018.06.013.

Cite as: https://hdl.handle.net/21.11116/0000-0003-4C5E-0

Abstract

Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbing additional genes or pathways, during iPSC generation from mouse embryonic fibroblasts. Analysis of these cells uncovered transcription factors (e.g., Tfap2c and Bex2) that are important for reprogramming but dispensable for pluripotency maintenance. Additionally, we observed striking patterns of chromatin hyperaccessibility at pluripotency loci, which preceded gene expression in poised intermediates. Finally, inspection of these hyperaccessible regions revealed an early wave of DNA demethylation that is uncoupled from de novo methylation of somatic regions late in reprogramming. Our study underscores the importance of investigating rare intermediates poised to produce iPSCs, provides insights into reprogramming mechanisms, and offers a valuable resource for the dissection of transcriptional and epigenetic dynamics intrinsic to cell fate change.