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Cell. 2015 Jul 16;162(2):412-424. doi: 10.1016/j.cell.2015.06.016.

Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency.

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
2
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
3
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Boston Children's Hospital and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston, MA 02115, USA.
4
Broad Institute, Cambridge, MA 02142, USA.
5
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
6
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: tarjei@broadinstitute.org.

Abstract

Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here, we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered re-activation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies. PAPERCLIP.

PMID:
26186193
PMCID:
PMC4511597
DOI:
10.1016/j.cell.2015.06.016
[Indexed for MEDLINE]
Free PMC Article

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