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Mechanisms and models of somatic cell reprogramming

Nature Reviews Genetics volume 14, pages 427–439 (2013)Cite this article

Subjects

Key Points

  • Insights gained from population-based and single-cell studies reveal two major phases during reprogramming.

  • OSK (OCT4, SOX2 and KLF4) factors act as 'pioneer' factors that open chromatin regions and allow the activation of those genes that are essential for establishment and maintenance of the pluripotent state. This promiscuous binding of OSK is also essential for the initiation of crucial processes for the reprogramming process such as proliferation and mesenchymal-to-epithelial transition (MET).

  • We present evidence supporting a model in which the reprogramming process contains an early stochastic phase that leads to the instigation of a second more deterministic phase that starts with the activation of Sox2.

  • How similar are induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs)? The available evidence has not settled whether the alterations seen in iPSCs are the result of the reprogramming process or whether they are due to pre-existing genetic and epigenetic differences among parental fibroblasts.

Abstract

Conversion of somatic cells to pluripotency by defined factors is a long and complex process that yields embryonic-stem-cell-like cells that vary in their developmental potential. To improve the quality of resulting induced pluripotent stem cells (iPSCs), which is important for potential therapeutic applications, and to address fundamental questions about control of cell identity, molecular mechanisms of the reprogramming process must be understood. Here we discuss recent discoveries regarding the role of reprogramming factors in remodelling the genome, including new insights into the function of MYC, and describe the different phases, markers and emerging models of reprogramming.

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Figure 1: Phases of the reprogramming process.
Figure 2: OSKM factors as pioneer factors for remodelling the epigenome.
Figure 3: Model of molecular events that precede iPSC formation.

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References

  1. Jaenisch, R. & Young, R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567–582 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yamanaka, S. & Blau, H. M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704–712 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pasque, V., Miyamoto, K. & Gurdon, J. B. Efficiencies and mechanisms of nuclear reprogramming. Cold Spring Harb. Symp. Quant. Biol. 75, 189–200 (2010).

    CAS  PubMed  Google Scholar 

  4. Vierbuchen, T. & Wernig, M. Molecular roadblocks for cellular reprogramming. Mol. Cell 47, 827–838 (2012).

    CAS  PubMed  Google Scholar 

  5. Buganim, Y. & Jaenisch, R. Transdifferentiation by defined factors as a powerful research tool to address basic biological questions. Cell Cycle 11, 4485–4486 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Stadtfeld, M. & Hochedlinger, K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 24, 2239–2263 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wakayama, S. et al. Equivalency of nuclear transfer-derived embryonic stem cells to those derived from fertilized mouse blastocysts. Stem Cells 24, 2023–2033 (2006).

    CAS  PubMed  Google Scholar 

  8. Brambrink, T., Hochedlinger, K., Bell, G. & Jaenisch, R. ES cells derived from cloned and fertilized blastocysts are transcriptionally and functionally indistinguishable. Proc. Natl Acad. Sci. USA 103, 933–938 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhao, X. Y. et al. iPS cells produce viable mice through tetraploid complementation. Nature 461, 86–90 (2009).

    CAS  PubMed  Google Scholar 

  10. Kang, L. Wang, J., Zhang, Y., Kou, Z. & Gao, S. iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5, 135–138 (2009).

    CAS  PubMed  Google Scholar 

  11. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  12. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Google Scholar 

  13. Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010).

    CAS  PubMed  Google Scholar 

  15. Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64–77 (2010). This paper describes the various phases (namely, initiation, maturation and stabilization) during the reprogramming process and sheds lights on the role of BMP signalling and the induction of MET during the initiation phase.

    CAS  PubMed  Google Scholar 

  16. Golipour, A. et al. A late transition in somatic cell reprogramming requires regulators distinct from the pluripotency network. Cell Stem Cell 11, 769–782 (2012).

    CAS  PubMed  Google Scholar 

  17. Polo, J. M. et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151, 1617–1632 (2012). This paper demonstrates the various pathways and genes involved in early, intermediate and late phases using enriched populations and single-cell approaches. It also shows the various epigenetic modifications that occur at early and late time points and the rescue of partially reprogramed cells by the addition of external factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hansson, J. et al. Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell Rep. 2, 1579–1592 (2012). This paper demonstrates the various pathways and proteins involved in early, intermediate and late phases using enriched populations.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, J., Nuebel, E., Daley, G. Q., Koehler, C. M. & Teitell, M. A. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 11, 589–595 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sancho-Martinez, I. & Izpisua Belmonte, J. C. Stem cells: surf the waves of reprogramming. Nature 493, 310–311 (2013).

    CAS  PubMed  Google Scholar 

  21. Araki, R. et al. Conversion of ancestral fibroblasts to induced pluripotent stem cells. Stem Cells 28, 213–220 (2010).

    CAS  PubMed  Google Scholar 

  22. Smith, Z. D., Nachman, I., Regev, A. & Meissner, A. Dynamic single-cell imaging of direct reprogramming reveals an early specifying event. Nature Biotech. 28, 521–526 (2010). This paper uses single-cell imaging to trace the rare cells that undergo reprogramming based on morphology.

    CAS  Google Scholar 

  23. Buganim, Y. et al. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150, 1209–1222 (2012). Using two complementary single-cell approaches, this study discovered early markers for reprogramming, the late deterministic phase that starts with the activation of Sox2 and shows iPSC formation without 'Yamanaka' factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Guo, G. et al. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev. Cell 18, 675–685 (2010).

    CAS  PubMed  Google Scholar 

  25. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Citri, A., Pang, Z. P., Sudhof, T. C., Wernig, M. & Malenka, R. C. Comprehensive qPCR profiling of gene expression in single neuronal cells. Nature Protoc. 7, 118–127 (2012).

    CAS  Google Scholar 

  27. Narsinh, K. H. et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J. Clin. Invest. 121, 1217–1221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nature Methods 5, 877–879 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009). This paper shows that all somatic cells have the potential to generate iPSCs by a process that involves stochastic events.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).

    CAS  PubMed  Google Scholar 

  31. Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).

    CAS  PubMed  Google Scholar 

  32. Fussner, E. et al. Constitutive heterochromatin reorganization during somatic cell reprogramming. EMBO J. 30, 1778–1789 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007).

    CAS  PubMed  Google Scholar 

  34. Schmidt, R. & Plath, K. The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. Genome Biol. 13, 251 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liang, G. & Zhang, Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res. 23, 49–69 (2013).

    CAS  PubMed  Google Scholar 

  36. Koche, R. P. et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8, 96–105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sridharan, R. et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell 136, 364–377 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Stadtfeld, M., Maherali, N., Breault, D. T. & Hochedlinger, K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2, 230–240 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ang, Y. S. et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145, 183–197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mansour, A. A. et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 488, 409–413 (2012).

    CAS  PubMed  Google Scholar 

  42. Costa, Y. et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495, 370–374 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Doege, C. A. et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488, 652–655 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gao, Y. et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 12, 453–469 (2013).

    CAS  PubMed  Google Scholar 

  45. Singhal, N. et al. Chromatin-remodeling components of the BAF complex facilitate reprogramming. Cell 141, 943–955 (2010).

    CAS  PubMed  Google Scholar 

  46. Liang, G., He, J. & Zhang, Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nature Cell Biol. 14, 457–466 (2012).

    CAS  PubMed  Google Scholar 

  47. Wang, T. et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9, 575–587 (2011).

    CAS  PubMed  Google Scholar 

  48. Onder, T. T. et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature 483, 598–602 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Schotta, G., Ebert, A. & Reuter, G. SU(VAR)3-9 is a conserved key function in heterochromatic gene silencing. Genetica 117, 149–158 (2003).

    CAS  PubMed  Google Scholar 

  50. Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell 151, 994–1004 (2012). This paper raises the notion that OSK proteins are pioneer factors that guide reprogramming through promiscuous binding to distal elements that lack pre-existing histone modifications.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kagey, M. H. et al. Mediator and Cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin, C., Garruss, A. S., Luo, Z., Guo, F. & Shilatifard, A. The RNA Pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. Cell 152, 144–156 (2012).

    PubMed  PubMed Central  Google Scholar 

  53. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Efe, J. A. et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nature Cell Biol. 13, 215–222 (2011).

    CAS  PubMed  Google Scholar 

  55. Kim, J. et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc. Natl Acad. Sci. USA 108, 7838–7843 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Anokye-Danso, F. et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376–388 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Maekawa, M. et al. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 474, 225–229 (2011).

    CAS  PubMed  Google Scholar 

  58. Liao, B. et al. MicroRNA cluster 302–367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J. Biol. Chem. 286, 17359–17364 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Subramanyam, D. et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nature Biotech. 29, 443–448 (2011).

    CAS  Google Scholar 

  60. Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Eilers, M. & Eisenman, R. N. Myc's broad reach. Genes Dev. 22, 2755–2766 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nature Rev. Cancer 8, 976–990 (2008).

    CAS  Google Scholar 

  63. Blackwood, E. M. & Eisenman, R. N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251, 1211–1217 (1991).

    CAS  PubMed  Google Scholar 

  64. Wernig, M., Meissner, A., Cassady, J. P. & Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10–12 (2008).

    CAS  PubMed  Google Scholar 

  65. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotech. 26, 101–106 (2008).

    CAS  Google Scholar 

  66. Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Lin, C. Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012). References 67 and 68 revisit the role of MYC during transcription regulation and show that MYC is a global gene amplifier.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang, Y. et al. Model-based analysis of ChIP-seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  70. Bouchard, C., Marquardt, J., Bras, A., Medema, R. H. & Eilers, M. Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J. 23, 2830–2840 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Eberhardy, S. R. & Farnham, P. J. c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. J. Biol. Chem. 276, 48562–48571 (2001).

    CAS  PubMed  Google Scholar 

  72. Carey, B. W. et al. Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9, 588–598 (2011).

    CAS  PubMed  Google Scholar 

  73. Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Tiemann, U. et al. Optimal reprogramming factor stoichiometry increases colony numbers and affects molecular characteristics of murine induced pluripotent stem cells. Cytometry A 79, 426–435 (2011).

    PubMed  Google Scholar 

  75. Yamaguchi, S., Hirano, K., Nagata, S. & Tada, T. Sox2 expression effects on direct reprogramming efficiency as determined by alternative somatic cell fate. Stem Cell Res. 6, 177–186 (2011).

    CAS  PubMed  Google Scholar 

  76. Chen, J. et al. Rational optimization of reprogramming culture conditions for the generation of induced pluripotent stem cells with ultra-high efficiency and fast kinetics. Cell Res. 21, 884–894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Esteban, M. A. et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71–79 (2010).

    CAS  PubMed  Google Scholar 

  78. Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotech. 26, 795–797 (2008).

    CAS  Google Scholar 

  79. Ichida, J. K. et al. A small-molecule inhibitor of TGF-βsignaling replaces SOX2 in reprogramming by inducing nanog. Cell Stem Cell 5, 491–503 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Maherali, N. & Hochedlinger, K. Tgfβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr. Biol. 19, 1718–1723 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Esteban, M. A. & Pei, D. Vitamin C improves the quality of somatic cell reprogramming. Nature Genet. 44, 366–367 (2012).

    CAS  PubMed  Google Scholar 

  82. Stadtfeld, M. et al. Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nature Genet. 44, 398–405 (2012).

    CAS  PubMed  Google Scholar 

  83. Lengner, C. J. et al. Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141, 872–883 (2010).

    CAS  PubMed  Google Scholar 

  84. Greder, L. V. et al. Brief report: analysis of endogenous Oct4 activation during induced pluripotent stem cell reprogramming using an inducible Oct4 lineage label. Stem Cells 30, 2596–2601 (2012).

    PubMed  PubMed Central  Google Scholar 

  85. Pennisi, E. & Williams, N. Will Dolly send in the clones? Science 275, 1415–1416 (1997).

    CAS  PubMed  Google Scholar 

  86. Hochedlinger, K. & Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002).

    CAS  PubMed  Google Scholar 

  87. Wakao, S., Kitada, M. & Dezawa, M. The elite and stochastic model for iPS cell generation: multilineage-differentiating stress enduring (Muse) cells are readily reprogrammable into iPS cells. Cytometry A 83, 18–26 (2013).

    PubMed  Google Scholar 

  88. Yamanaka, S. Elite and stochastic models for induced pluripotent stem cell generation. Nature 460, 49–52 (2009).

    CAS  PubMed  Google Scholar 

  89. Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699–702 (2008).

    CAS  PubMed  Google Scholar 

  90. Hanna, J. et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250–264 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Seki, T. et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11–14 (2010).

    CAS  PubMed  Google Scholar 

  92. Meissner, A., Wernig, M. & Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nature Biotech. 25, 1177–1181 (2007).

    CAS  Google Scholar 

  93. Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nature Genet. 45, 34–42 (2012).

    PubMed  Google Scholar 

  94. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhu, J. et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell 152, 642–654 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Takeuchi, J. K. & Bruneau, B. G. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459, 708–711 (2009). This paper describes the fluidity of chromatin in ESCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Pijnappel, W. W. et al. A central role for TFIID in the pluripotent transcription circuitry. Nature 495, 516–519 (2013).

    PubMed  Google Scholar 

  99. Mattout, A., Biran, A. & Meshorer, E. Global epigenetic changes during somatic cell reprogramming to iPS cells. J. Mol. Cell. Biol. 3, 341–350 (2011).

    PubMed  Google Scholar 

  100. Zuo, B. et al. Influences of lamin A levels on induction of pluripotent stem cells. Biol. Open 1, 1118–1127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Suhr, S. T. et al. Mitochondrial rejuvenation after induced pluripotency. PLoS ONE 5, e14095 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Van Haute, L., Spits, C., Geens, M., Seneca, S. & Sermon, K. Human embryonic stem cells commonly display large mitochondrial DNA deletions. Nature Biotech. 31, 20–23 (2013).

    CAS  Google Scholar 

  103. Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011).

    CAS  PubMed  Google Scholar 

  104. Laurent, L. C. et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106–118 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).

    CAS  PubMed  Google Scholar 

  107. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009).

    CAS  PubMed  Google Scholar 

  109. Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nature Cell Biol. 13, 541–549 (2011).

    CAS  PubMed  Google Scholar 

  110. Bar-Nur, O., Russ, H. A., Efrat, S. & Benvenisty, N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9, 17–23 (2011).

    CAS  PubMed  Google Scholar 

  111. Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotech. 28, 848–855 (2010).

    CAS  Google Scholar 

  112. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kim, K. et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nature Biotech. 29, 1117–1119 (2011).

    CAS  Google Scholar 

  114. Chin, M. H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Phanstiel, D. H. et al. Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nature Methods 8, 821–827 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Newman, A. M. & Cooper, J. B. Lab-specific gene expression signatures in pluripotent stem cells. Cell Stem Cell 7, 258–262 (2010).

    CAS  PubMed  Google Scholar 

  117. Guenther, M. G. et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cheng, L. et al. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 10, 337–344 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Vitale, A. M. et al. Variability in the generation of induced pluripotent stem cells: importance for disease modeling. Stem Cells Transl. Med. 1, 641–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Gonzalez, F. et al. Homologous recombination DNA repair genes play a critical role in reprogramming to a pluripotent state. Cell Rep. 3, 651–660 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Abyzov, A. et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492, 438–442 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Soldner, F. & Jaenisch, R. Medicine. iPSC disease modeling. Science 338, 1155–1156 (2012).

    PubMed  Google Scholar 

  124. Jaenisch, R. Nuclear cloning and direct reprogramming: the long and the short path to stockholm. Cell Stem Cell 11, 744–747 (2012).

    CAS  PubMed  Google Scholar 

  125. Han, J. et al. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463, 1096–1100 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Jiang, J. et al. Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res. 23, 92–106 (2012).

    PubMed  PubMed Central  Google Scholar 

  127. Zhao, X. Y., Lv, Z., Li, W., Zeng, F. & Zhou, Q. Production of mice using iPS cells and tetraploid complementation. Nature Protoc. 5, 963–971 (2010).

    CAS  Google Scholar 

  128. Silva, J. et al. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol. 6, e253 (2008).

    PubMed  PubMed Central  Google Scholar 

  129. Yuan, X. et al. Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells 29, 549–553 (2011).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Dawlaty, A. Soufi and K. Zaret for insightful comments on the manuscript. Y.B. is supported by a US National Institutes of Health (NIH) Kirschstein National Research Service Award (1 F32 GM099153-01A1). D.A.F. is a Vertex Scholar and was supported by a US National Science Foundation Graduate Research Fellowship and Jerome and Florence Brill Graduate Student Fellowship. R.J. is supported by US NIH grants R37-CA084198 and RO1-CA087869.

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Yosef Buganim, Dina A. Faddah & Rudolf Jaenisch

  2. Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, 02139, Massachusetts, USA

    Dina A. Faddah & Rudolf Jaenisch

Authors
  1. Yosef Buganim
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  2. Dina A. Faddah
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  3. Rudolf Jaenisch
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Correspondence to Rudolf Jaenisch.

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Competing interests

Rudolf Jaenisch is an adviser to Stemgent and a cofounder of Fate Therapeutics. Yosef Buganim and Dina A. Faddah declare no competing financial interests.

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Glossary

Epigenome

Heritable changes in chromatin (such as histone post-translational modifications and DNA methylation) that affect gene expression.

Reprogramming

Conversion of one cell type to another cell type by transcription factors or chemically defined media.

Cell plasticity

The ability of a cell to acquire a new identity and to adopt an alternative fate when exposed to different conditions.

Deterministic

A collection of actions during the reprogramming process that must occur in a particular order (that is, activation or silencing of different combinations of genes) before induced pluripotent stem cell formation.

Transcription-factor-mediated reprogramming

Conversion of a somatic cell to a pluripotent cell using defined transcription factors.

Developmental potential

The sum of all possible fates that a cell can undergo under any experimental condition.

Refractory

Unresponsive to a stimulus or unable to bind a transcription factor.

Cell heterogeneity

Variation among cells that occurs owing to gene expression differences.

Single-molecule mRNA fluorescent in situ hybridization

(sm-mRNA-FISH). An in situ hybridization method capable of detecting individual mRNA molecules, thus permitting the precise quantification and localization of mRNA within a single cell.

Stochastic

In this context, this term refers to an unpredictable and random action that leads at some point to the activation or repression of genes that will then set a cell on the path to becoming an induced pluripotent stem cell.

Rate-limiting

In this context, this term refers to a step that is responsible for the low efficiency of the reprogramming process. Reprogrammable cells must pass this step to instigate the late hierarchical phase and to become fully reprogramed. This step determines the length of the reprogramming process.

Hierarchical

An arrangement of items that are directly or indirectly linked. For reprogramming, this is a predictable sequence of gene activations or repressions.

Chromatin modifiers

Proteins that can modify chromatin architecture and thereby control gene expression.

Pioneer factors

A subset of transcription factors that initially accesses silent chromatin and directs the binding of other transcription factors during embryonic development. Pioneer factors (OSK proteins during reprogramming) create a hyperdynamic chromatin state.

Promiscuous binding

In this context, the multiple distal genomic sites initially occupied by OSK proteins that do not correspond to the distal genomic regions that are bound by these pluripotency factors in embryonic stem cells.

Factor stoichiometry

Different levels of and the ratios between reprogramming factors (OSKM) in single cells.

Mediator

A complex comprised of multiple protein subunits that function as a transcriptional co-activator to increase gene expression.

Super enhancers

Expansive regions of DNA that are bound by large amounts of Mediator and other proteins to enhance the transcription of genes.

Transcriptional amplifiers

Proteins such as MYC that can increase expression from any active promoter.

Predictive early markers

Genes that are activated early in the reprogramming process in rare cells that have a higher probability of activating the Sox2 locus and to become fully reprogrammed induced pluripotent stem cells.

Pluripotency initiating factors

(PIFs). Protein factors that are responsible for triggering the late deterministic phase responsible for transitioning to the pluripotent state.

Hyperdynamic

This term describes a state of dynamic chromatin characterized by hypermobility of chromatin-associated proteins in pluripotent cells.

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Buganim, Y., Faddah, D. & Jaenisch, R. Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 14, 427–439 (2013). https://doi.org/10.1038/nrg3473

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