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Cell. 2014 Dec 18;159(7):1681-97. doi: 10.1016/j.cell.2014.11.040.

X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency.

Author information

1
Department of Biological Chemistry, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
2
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
4
Department of Advanced Bioscience, Graduate School of Agriculture, Kinki University, 3327-204 Nakamachi, Nara, 631-8505, Japan.
5
Department of Stem Cell Engineering, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
6
Department of Biological Chemistry, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: kplath@mednet.ucla.edu.

Abstract

Reprogramming to iPSCs resets the epigenome of somatic cells, including the reversal of X chromosome inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X inactivation, whereas others are uncoupled from this sequence. Among the latter, DNA methylation has an extraordinary long persistence on the Xi during reprogramming, and, like Xist expression, is erased only after pluripotency genes are activated. Mechanistically, XCR requires both DNA demethylation and Xist silencing, ensuring that only cells undergoing faithful reprogramming initiate XCR. Our study defines the epigenetic state of multiple sequential reprogramming intermediates and establishes a paradigm for studying cell fate transitions during reprogramming.

PMID:
25525883
PMCID:
PMC4282187
DOI:
10.1016/j.cell.2014.11.040
[Indexed for MEDLINE]
Free PMC Article

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