Epigenetic memory in induced pluripotent stem cells

K. Kim, A. Doi, B. Wen, K. Ng, R. Zhao, P. Cahan, J. Kim, M. J. Aryee, H. Ji, L. I. R. Ehrlich, A. Yabuuchi, A. Takeuchi, K. C. Cunniff, H. Hongguang, S. Mckinney-Freeman, O. Naveiras, T. J. Yoon, R. A. Irizarry, N. Jung, J. Seita, J. Hanna, P. Murakami, R. Jaenisch, R. Weissleder, S. H. Orkin, I. L. Weissman, A. P. Feinberg () and G. Q. Daley ()
Additional contact information
K. Kim: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
A. Doi: Johns Hopkins University School of Medicine
B. Wen: Johns Hopkins University School of Medicine
K. Ng: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
R. Zhao: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
P. Cahan: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
J. Kim: Howard Hughes Medical Institute, Children’s Hospital Boston and Dana Farber Cancer Institute
M. J. Aryee: Johns Hopkins Bloomberg School of Public Health, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
H. Ji: Johns Hopkins University School of Medicine
L. I. R. Ehrlich: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
A. Yabuuchi: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
A. Takeuchi: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
K. C. Cunniff: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
H. Hongguang: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
S. Mckinney-Freeman: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
O. Naveiras: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute
T. J. Yoon: Center for Systems Biology, Massachusetts General Hospital/Harvard Medical School, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
R. A. Irizarry: Johns Hopkins University School of Medicine
N. Jung: Johns Hopkins University School of Medicine
J. Seita: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
J. Hanna: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
P. Murakami: Johns Hopkins University School of Medicine
R. Jaenisch: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
R. Weissleder: Center for Systems Biology, Massachusetts General Hospital/Harvard Medical School, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
S. H. Orkin: Howard Hughes Medical Institute, Children’s Hospital Boston and Dana Farber Cancer Institute
I. L. Weissman: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
A. P. Feinberg: Johns Hopkins University School of Medicine
G. Q. Daley: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute

Nature, 2010, vol. 467, issue 7313, 285-290

Abstract: Abstract Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an ‘epigenetic memory’ of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.

Date: 2010
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DOI: 10.1038/nature09342

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