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      Epigenetic memory in induced pluripotent stem cells

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          Summary

          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. These two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, by different mechanisms and kinetics, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low passage induced pluripotent stem cells (iPSC) derived by factor-based reprogramming harbor residual DNA methylation signatures characteristic of their somatic tissue of origin, which favors 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 iPSC 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 iPSC, consistent with more effective reprogramming. Our data demonstrate that factor-based reprogramming can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modeling or treatment.

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          In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.

          Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells-derived from mouse fibroblasts-can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.
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            Dissecting direct reprogramming through integrative genomic analysis.

            Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.
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              Direct cell reprogramming is a stochastic process amenable to acceleration

              Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming is a continuous stochastic process where almost all donor cells eventually give rise to iPSCs upon continued growth and transcription factor expression. Additional inhibition the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPSC formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell division rate independent manner. Quantitative analyses define distinct cell division rate dependent and independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                18 July 2011
                16 September 2010
                05 August 2011
                : 467
                : 7313
                : 285-290
                Affiliations
                [1 ]Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children’s Hospital Boston and Dana Farber Cancer Institute; Division of Hematology, Brigham and Women’s Hospital; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Harvard Stem Cell Institute; Boston, MA 02115, USA
                [2 ]Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [3 ]Department of Pediatric Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston and Dana Farber Cancer Institute; Boston, MA 02115, USA
                [4 ]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
                [5 ]Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
                [6 ]Center for Systems Biology, Massachusetts General Hospital / Harvard Medical School, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA
                [7 ]Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                Author notes
                [#]

                Present address: Department of Applied Bioscience, CHA University, Seoul 135-081, Korea

                Author Information CHARM microarray data are deposited at the Gene Expression Omnibus ( http://www.ncbi.nlm.nih.gov/geo) under accession number GSE22851. Reprints and permissions information is available at www.nature.com/reprints. G.Q.D. is a member of the Scientific Advisory Boards of MPM Capital, Inc., Epizyme, Inc., and iPierian, Inc. R.J. is a member of the Scientific Advisory Boards of Fate Therapeutics, Inc. and StemGent, Inc. I.R.W is a member of the Scientific Advisory Boards of Cellerant, Inc, and Stem Cells, Inc. Readers are welcome to comment on the online version of this article at www.nature.com/nature. Correspondence and requests for materials should be addressed to A.P.F ( afeinberg@ 123456jhu.edu ) and G.Q.D. ( george.daley@ 123456childrens.harvard.edu ).

                [* ]To Whom Correspondence should be Addressed: George Q. Daley, Phone: (617) 919-2013, Fax: (617) 730-0222, george.daley@ 123456childrens.harvard.edu , Andrew P. Feinberg, Phone: (410) 614-3489, Fax: (410) 614-9819, afeinberg@ 123456jhu.edu
                Article
                nihpa221287
                10.1038/nature09342
                3150836
                20644535
                12f967a7-5a47-4ec9-a129-1de2d921e3e3

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                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: RC2 HL102815-01 || HL
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM083084-04 || GM
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK070055-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK059279-10 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK059279-02 || DK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: K99 HL093212-02 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: K99 HL093212-01 || HL
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000256-01 || OD
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