An Insight into Reprogramming Barriers to iPSC Generation

  • Krishna Kumar Haridhasapavalan
  • Khyati Raina
  • Chandrima Dey
  • Poulomi Adhikari
  • Rajkumar P. ThummerEmail author


Derivation of induced Pluripotent Stem Cells (iPSCs) by reprogramming somatic cells to a pluripotent state has revolutionized stem cell research. Ensuing this, various groups have used genetic and non-genetic approaches to generate iPSCs from numerous cell types. However, achieving a pluripotent state in most of the reprogramming studies is marred by serious limitations such as low reprogramming efficiency and slow kinetics. These limitations are mainly due to the presence of potent barriers that exist during reprogramming when a mature cell is coaxed to achieve a pluripotent state. Several studies have revealed that intrinsic factors such as non-optimal stoichiometry of reprogramming factors, specific signaling pathways, cellular senescence, pluripotency-inhibiting transcription factors and microRNAs act as a roadblock. In addition, the epigenetic state of somatic cells and specific epigenetic modifications that occur during reprogramming also remarkably impede the generation of iPSCs. In this review, we present a comprehensive overview of the barriers that inhibit reprogramming and the understanding of which will pave the way to develop safe strategies for efficient reprogramming.


induced Pluripotent Stem Cells Cell reprogramming Reprogramming barriers/roadblocks Transcription factors Epigenetics 



We thank all the members of the Laboratory for Stem Cell Engineering and Regenerative Medicine (SCERM) for their excellent support. This work was supported by North Eastern Region – Biotechnology Programme Management Cell (NERBPMC), Department of Biotechnology, Government of India (BT/PR16655/NER/95/132/2015) and also by IIT Guwahati Institutional Top-Up on Start-Up Grant. The authors sincerely apologize to all scientists whose research could not be cited in this review due to space restrictions.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no potential conflicts of interests.


  1. 1.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.CrossRefGoogle Scholar
  2. 2.
    Seifinejad, A., Tabebordbar, M., Baharvand, H., Boyer, L. A., & Hosseini Salekdeh, G. (2010). Progress and promise towards safe induced pluripotent stem cells for therapy. Stem Cell Reviews and Reports, 6(2), 297–306.CrossRefGoogle Scholar
  3. 3.
    Young, W. (2012). Patient-specific induced pluripotent stem cells as a platform for disease modeling, drug discovery and precision personalized medicine. Journal of Stem Cell Research & Therapy, 01(S10), 2.CrossRefGoogle Scholar
  4. 4.
    Singh, V. K., Kalsan, M., Kumar, N., Saini, A., & Chandra, R. (2015). Induced pluripotent stem cells: Applications in regenerative medicine, disease modeling, and drug discovery. Frontiers in Cell and Developmental Biology, 3, 2.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Omole, A. E., & Fakoya, A. O. J. (2018). Ten years of progress and promise of induced pluripotent stem cells: Historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ, 6, e4370.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Patel, M., & Yang, S. (2010). Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Reviews and Reports, 6(3), 367–380.CrossRefGoogle Scholar
  7. 7.
    Walia, B., Satija, N., Tripathi, R. P., & Gangenahalli, G. U. (2012). Induced pluripotent stem cells: Fundamentals and applications of the reprogramming process and its ramifications on regenerative medicine. Stem Cell Reviews and Reports, 8(1), 100–115.CrossRefGoogle Scholar
  8. 8.
    Hu, K. (2014). All roads lead to induced pluripotent stem cells: The technologies of iPSC generation. Stem Cells and Development, 23(12), 1285–1300.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Chhabra, A. (2017). Derivation of human induced pluripotent stem cell (iPSC) lines and mechanism of pluripotency: Historical perspective and recent advances. Stem Cell Reviews and Reports, 13(6), 757–773.CrossRefGoogle Scholar
  10. 10.
    Saha, B., Borgohain, M. P., Dey, C., & Thummer, R. P. (2018). iPS cell generation: Current and future challenges. Annals of Stem Cell Research and Therapy, 1(2), 1007.Google Scholar
  11. 11.
    Borgohain, M. P., Haridhasapavalan, K. K., Dey, C., Adhikari, P., & Thummer, R. P. (2019). An insight into DNA-free reprogramming approaches to generate integration-free induced pluripotent stem cells for prospective biomedical applications. Stem Cell Reviews and Reports, 15(2), 286–313.CrossRefGoogle Scholar
  12. 12.
    Haridhasapavalan, K. K., Borgohain, M. P., Dey, C., Saha, B., Narayan, G., Kumar, S., & Thummer, R. P. (2018). An insight into non-integrative gene delivery approaches to generate transgene-free induced pluripotent stem cells. Gene, 686, 146–159.PubMedCrossRefGoogle Scholar
  13. 13.
    Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.CrossRefGoogle Scholar
  14. 14.
    Sridharan, R., Tchieu, J., Mason, M. J., Yachechko, R., & Kuoy, E. (2009). Resource role of the Murine reprogramming factors in the induction of pluripotency. Cell, 136(2), 364–377.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Papapetrou, E. P., Tomishima, M. J., Chambers, S. M., Mica, Y., Reed, E., & Menon, J. (2009). Stoichiometric and temporal requirements of Oct4 , Sox2 , Klf4 , and c-Myc expression for efficient human iPSC induction and differentiation. Proceedings of the National Academy of Sciences USA, 106(31), 12759–12764.CrossRefGoogle Scholar
  16. 16.
    Tiemann, U., Sgodda, M., Warlich, E., Ballmaier, M., Schöler, H. R., Schambach, A., & Cantz, T. (2011). Optimal reprogramming factor stoichiometry increases colony numbers and affects molecular characteristics of murine induced pluripotent stem cells. Cytometry Part A, 79(6), 426–435.CrossRefGoogle Scholar
  17. 17.
    Carey, B. W., Markoulaki, S., Hanna, J. H., Faddah, D. A., Buganim, Y., Kim, J., et al. (2011). Short article reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Stem Cells, 9(6), 588–598.Google Scholar
  18. 18.
    Stefanovic, S., & Pucéat, M. (2007). Oct-3/4: Not just a gatekeeper of pluripotency for embryonic stem cell, a cell fate instructor through a gene dosage effect. Cell Cycle, 6(1), 8–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Karwacki-Neisius, V., Göke, J., Osorno, R., Halbritter, F., Ng, J. H., Weiße, A. Y., et al. (2013). Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog. Cell Stem Cell, 12(5), 531–545.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Stefanovic, S., Abboud, N., Désilets, S., Nury, D., Cowan, C., & Pucéat, M. (2009). Interplay of Oct4 with Sox2 and Sox17: A molecular switch from stem cell pluripotency to specifying a cardiac fate. Journal of Cell Biology, 186(5), 665–673.PubMedCrossRefGoogle Scholar
  21. 21.
    Wen, W., Zhang, J.-P., Xu, J., Su, R. J., Neises, A., Ji, G.-Z., et al. (2016). Enhanced generation of integration-free iPSCs from human adult peripheral blood mononuclear cells with an optimal combination of episomal vectors. Stem Cell Reports, 6(6), 873–884.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Schmitt, C. E., Morales, B. M., Schmitz, E. M. H., Hawkins, J. S., Lizama, C. O., Zape, J. P., et al. (2017). Fluorescent tagged episomals for stoichiometric induced pluripotent stem cell reprogramming. Stem Cell Research and Therapy, 8(1), 132.PubMedCrossRefGoogle Scholar
  23. 23.
    Nagamatsu, G., Saito, S., Kosaka, T., Takubo, K., Kinoshita, T., Oya, M., et al. (2012). Optimal ratio of transcription factors for somatic cell reprogramming. Journal of Biological Chemistry, 287(43), 36273–36282.PubMedCrossRefGoogle Scholar
  24. 24.
    Yamaguchi, S., Hirano, K., Nagata, S., & Tada, T. (2011). Sox2 expression effects on direct reprogramming efficiency as determined by alternative somatic cell fate. Stem Cell Research, 6(2), 177–186.PubMedCrossRefGoogle Scholar
  25. 25.
    Sommer, C. A., Christodoulou, C., Gianotti-Sommer, A., Shen, S. S., Sailaja, B. S., Hezroni, H., et al. (2012). Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLOS ONE, 7(12), 1–10.CrossRefGoogle Scholar
  26. 26.
    Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920.PubMedCrossRefGoogle Scholar
  27. 27.
    Vogt, P. K. (2002). Fortuitous convergences: The beginnings of JUN. Nature Reviews Cancer, 2(6), 465–469.PubMedCrossRefGoogle Scholar
  28. 28.
    Hilberg, F., Aguzzi, A., Howells, N., & Wagner, E. F. (1993). c-Jun is essential for normal mouse development and hepatogenesis. Nature, 365(6442), 179.PubMedCrossRefGoogle Scholar
  29. 29.
    Liu, J., Han, Q., Peng, T., Peng, M., Wei, B., Li, D., et al. (2015). The oncogene c-Jun impedes somatic cell reprogramming. Nature Cell Biology, 17(7), 856–867.PubMedCrossRefGoogle Scholar
  30. 30.
    Schreiber, M., Kolbus, A., Piu, F., Szabowski, A., Möhle-Steinlein, U., Tian, J., et al. (1999). Control of cell cycle progression by c-Jun is p53 dependent. Genes and Development, 13(5), 607–619.PubMedCrossRefGoogle Scholar
  31. 31.
    Li, R., Liang, J., Ni, S., Zhou, T., Qing, X., Li, H., et al. (2010). A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell, 7(1), 51–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Samavarchi-Tehrani, P., Golipour, A., David, L., Sung, H. K., Beyer, T. A., Datti, A., et al. (2010). Functional genomics reveals a BMP-Driven mesenchymal-to-Epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell, 7(1), 64–77.PubMedCrossRefGoogle Scholar
  33. 33.
    Li, D., Liu, J., Yang, X., Zhou, C., Guo, J., Wu, C., et al. (2017). Chromatin accessibility dynamics during iPSC reprogramming. Cell Stem Cell, 21(6), 819–833.e6.PubMedCrossRefGoogle Scholar
  34. 34.
    Cadigan, K. M., & Waterman, M. L. (2012). TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harbor Perspectives in Biology, 4(11), a007906.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Pereira, L., Yi, F., & Merrill, B. J. (2006). Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Molecular and Cellular Biology, 26(20), 7479–7491.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Lluis, F., Ombrato, L., Pedone, E., Pepe, S., Merrill, B. J., & Cosma, M. P. (2011). T-cell factor 3 (Tcf3) deletion increases somatic cell reprogramming by inducing epigenome modifications. Proceedings of the National Academy of Sciences USA, 108(29), 11912–11917.CrossRefGoogle Scholar
  37. 37.
    Cole, M. F., Johnstone, S. E., Newman, J. J., Kagey, M. H., & Young, R. A. (2008). Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes and Development, 22(6), 746–755.PubMedCrossRefGoogle Scholar
  38. 38.
    Tam, W.-L., Lim, C. Y., Han, J., Zhang, J., Ang, Y.-S., Ng, H.-H., et al. (2008). T-Cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways. Stem Cells, 26(8), 2019–2031.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ye, S., Zhang, T., Tong, C., Zhou, X., He, K., Ban, Q., et al. (2017). Depletion of Tcf3 and Lef1 maintains mouse embryonic stem cell self-renewal. Biology Open, 6(4), 511–517.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ho, R., Papp, B., Hoffman, J. A., Merrill, B. J., & Plath, K. (2013). Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Reports, 3(6), 2113–2126.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Lin, D., Ippolito, G. C., Zong, R. T., Bryant, J., Koslovsky, J., & Tucker, P. (2007). Bright/ARID3A contributes to chromatin accessibility of the immunoglobulin heavy chain enhancer. Molecular Cancer, 6(1), 23.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Webb, C. F., Bryant, J., Popowski, M., Allred, L., Kim, D., Harriss, J., et al. (2011). The ARID family transcription factor bright is required for both hematopoietic stem cell and B lineage development. Molecular and Cellular Biology, 31(5), 1041–1053.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    An, G., Miner, C. A., Nixon, J. C., Kincade, P. W., Bryant, J., Tucker, P. W., & Webb, C. F. (2010). Loss of bright/ARID3a function promotes developmental plasticity. Stem Cells, 28(9), 1560–1567.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Popowski, M., Templeton, T. D., Lee, B. K., Rhee, C., Li, H., Miner, C., et al. (2014). Bright/Arid3A acts as a barrier to somatic cell reprogramming through direct regulation of Oct4, Sox2, and Nanog. Stem Cell Reports, 2(1), 26–35.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Serrano, F., Calatayud, C. F., Blazquez, M., Torres, J., Castell, J. V., & Bort, R. (2013). Gata4 blocks somatic cell reprogramming by directly repressing Nanog. Stem Cells, 31(1), 71–82.PubMedCrossRefGoogle Scholar
  46. 46.
    Fidalgo, M., Faiola, F., Pereira, C.-F., Ding, J., Saunders, A., Gingold, J., et al. (2012). Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming. Proceedings of the National Academy of Sciences USA, 109(40), 16202–16207.CrossRefGoogle Scholar
  47. 47.
    Ma, H., Ow, J. R., Tan, B. C. P., Goh, Z., Feng, B., Loh, Y. H., et al. (2014). The dosage of Patz1 modulates reprogramming process. Scientific Reports, 4, 7519.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313.PubMedCrossRefGoogle Scholar
  49. 49.
    Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., et al. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature, 448(7151), 318.CrossRefGoogle Scholar
  50. 50.
    Shu, J., Zhang, K., Zhang, M., Yao, A., Shao, S., Du, F., et al. (2015). GATA family members as inducers for cellular reprogramming to pluripotency. Cell Research, 25(2), 169–180.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Xue, Y., Wong, J., Moreno, G. T., Young, M. K., Côté, J., & Wang, W. (1998). NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Molecular Cell, 2(6), 851–861.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang, W., Aubert, A., Gomez de Segura, J. M., Karuppasamy, M., Basu, S., Murthy, A. S., et al. (2016). The nucleosome remodeling and deacetylase complex NuRD is built from preformed catalytically active sub-modules. Journal of Molecular Biology, 428(14), 2931–2942.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A. E., & Melton, D. A. (2008). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology, 26(7), 795–797.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Silva, J., Nichols, J., Theunissen, T. W., Guo, G., van Oosten, A. L., Barrandon, O., et al. (2009). Nanog is the gateway to the pluripotent ground state. Cell, 138(4), 722–737.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Allouba, M. H., ElGuindy, A. M., Krishnamoorthy, N., Yacoub, M. H., & Aguib, Y. E. (2015). NaNog: A pluripotency homeobox (master) molecule. Global Cardiology Science & Practice, 2015(3), 36.CrossRefGoogle Scholar
  56. 56.
    Mikkelsen, T. S., Hanna, J., Zhang, X., Ku, M., Wernig, M., Schorderet, P., et al. (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature, 454(7200), 49–55.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Qin, H., Diaz, A., Blouin, L., Lebbink, R. J., Patena, W., Tanbun, P., et al. (2014). Systematic identification of barriers to human iPSC generation. Cell, 158(2), 449–461.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Chronis, C., Fiziev, P., Papp, B., Butz, S., Bonora, G., Sabri, S., et al. (2017). Cooperative binding of transcription factors orchestrates reprogramming. Cell, 168(3), 442–459.e20.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Knaupp, A. S., Buckberry, S., Pflueger, J., Lim, S. M., Ford, E., Larcombe, M. R., et al. (2017). Transient and permanent reconfiguration of chromatin and transcription factor occupancy drive reprogramming. Cell Stem Cell, 21(6), 834–845.e6.PubMedCrossRefGoogle Scholar
  60. 60.
    Meissner, A., Wernig, M., & Jaenisch, R. (2007). Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nature Biotechnology, 25(10), 1177–1181.PubMedCrossRefGoogle Scholar
  61. 61.
    Maherali, N., & Hochedlinger, K. (2009). Tgfβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Current Biology, 19(20), 1718–1723.PubMedCrossRefGoogle Scholar
  62. 62.
    Subramanyam, D., Lamouille, S., Judson, R. L., Liu, J. Y., Bucay, N., Derynck, R., & Blelloch, R. (2011). Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nature Biotechnology, 29(5), 443–448.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Ichida, J. K., Blanchard, J., Lam, K., Son, E. Y., Chung, J. E., Egli, D., et al. (2009). A small-molecule inhibitor of Tgf-β signaling replaces Sox2 in reprogramming by inducing Nanog. Cell Stem Cell, 5(5), 491–503.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Vidal, S. E., Amlani, B., Chen, T., Tsirigos, A., & Stadtfeld, M. (2014). Combinatorial modulation of signaling pathways reveals cell-type-specific requirements for highly efficient and synchronous iPSC reprogramming. Stem Cell Reports, 3(4), 574–584.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Yuan, X., Wan, H., Zhao, X., Zhu, S., Zhou, Q., & Ding, S. (2011). Brief report: Combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells, 29(3), 549–553.PubMedCrossRefGoogle Scholar
  66. 66.
    Varelas, X. (2014). The hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development (Cambridge), 141(8), 1614–1626.CrossRefGoogle Scholar
  67. 67.
    Ramos, A., & Camargo, F. D. (2012). The Hippo signaling pathway and stem cell biology. Trends in Cell Biology, 22(7), 339–346.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tamm, C., Böwer, N., & Annerén, C. (2011). Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF. Journal of Cell Science, 124(7), 1136–1144.PubMedCrossRefGoogle Scholar
  69. 69.
    Lian, I., Kim, J., Okazawa, H., Zhao, J., Zhao, B., Yu, J., et al. (2010). The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes and Development, 24(11), 1106–1118.PubMedCrossRefGoogle Scholar
  70. 70.
    Chia, N. Y., Chan, Y. S., Feng, B., Lu, X., Orlov, Y. L., Moreau, D., et al. (2010). A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature, 468(7321), 316–320.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Qin, H., Blaschke, K., Wei, G., Ohi, Y., Blouin, L., Qi, Z., et al. (2012). Transcriptional analysis of pluripotency reveals the hippo pathway as a barrier to reprogramming. Human Molecular Genetics, 21(9), 2054–2067.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Varelas, X., Sakuma, R., Samavarchi-Tehrani, P., Peerani, R., Rao, B. M., Dembowy, J., et al. (2008). TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nature Cell Biology, 10(7), 837–848.PubMedCrossRefGoogle Scholar
  73. 73.
    Zhao, B., Li, L., Tumaneng, K., Wang, C.-Y., & Guan, K.-L. (2010). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes and Development, 24(1), 72–85.PubMedCrossRefGoogle Scholar
  74. 74.
    Varelas, X., Miller, B. W., Sopko, R., Song, S., Gregorieff, A., Fellouse, F. A., et al. (2010). The Hippo pathway regulates Wnt/β-catenin signaling. Developmental Cell, 18(4), 579–591.PubMedCrossRefGoogle Scholar
  75. 75.
    Heallen, T., Zhang, M., Wang, J., Bonilla-Claudio, M., Klysik, E., Johnson, R. L., & Martin, J. F. (2011). Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science (New York, N.Y.), 332(6028), 458–461.CrossRefGoogle Scholar
  76. 76.
    Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., & Brivanlou, A. H. (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine, 10(1), 55–63.PubMedCrossRefGoogle Scholar
  77. 77.
    Hao, J., Li, T. G., Qi, X., Zhao, D. F., & Zhao, G. Q. (2006). WNT/β-catenin pathway up-regulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells. Developmental Biology, 290(1), 81–91.PubMedCrossRefGoogle Scholar
  78. 78.
    Xu, Z., Robitaille, A. M., Berndt, J. D., Davidson, K. C., Fischer, K. A., Mathieu, J., et al. (2016). Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells. Proceedings of the National Academy of Sciences USA, 113(42), E6382–E6390.CrossRefGoogle Scholar
  79. 79.
    Lluis, F., Pedone, E., Pepe, S., & Cosma, M. P. (2008). Periodic activation of Wnt/β-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell, 3(5), 493–507.PubMedCrossRefGoogle Scholar
  80. 80.
    Marson, A., Foreman, R., Chevalier, B., Bilodeau, S., Kahn, M., Young, R. A., & Jaenisch, R. (2008). Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell, 3(2), 132–135.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Silva, J., Barrandon, O., Nichols, J., Kawaguchi, J., Theunissen, T. W., & Smith, A. (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLOS Biology, 6(10), 2237–2247.CrossRefGoogle Scholar
  82. 82.
    Li, W., Zhou, H., Abujarour, R., Zhu, S., Young Joo, J., Lin, T., et al. (2009). Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells, 27(12), 2992–3000.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Li, Z., & Rana, T. M. (2012). A kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation. Nature Communications, 3, 1011–1085.CrossRefGoogle Scholar
  84. 84.
    Neganova, I., Shmeleva, E., Munkley, J., Chichagova, V., Anyfantis, G., Anderson, R., et al. (2016). JNK/SAPK signaling is essential for efficient reprogramming of human fibroblasts to induced pluripotent stem cells. Stem Cells, 34(5), 1198–1212.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Qi, X., Li, T.-G., Hao, J., Hu, J., Wang, J., Simmons, H., et al. (2004). BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proceedings of the National Academy of Sciences USA, 101(16), 6027–6032.CrossRefGoogle Scholar
  86. 86.
    Li, J., Wang, G., Wang, C., Zhao, Y., Zhang, H., Tan, Z., et al. (2007). MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. Differentiation, 75(4), 299–307.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Lai, W.-H., Ho, J. C.-Y., Lee, Y.-K., Ng, K.-M., Au, K.-W., Chan, Y.-C., et al. (2010). ROCK inhibition facilitates the generation of human-induced pluripotent stem cells in a defined, feeder-, and serum-free system. Cellular Reprogramming, 12(6), 641–653.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lin, Z., Liu, F., Shi, P., Song, A., Huang, Z., Zou, D., et al. (2018). Fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C. Stem Cell Research and Therapy, 9(1), 47.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Staerk, J., Lyssiotis, C. A., Medeiro, L. A., Bollong, M., Foreman, R. K., Zhu, S., et al. (2011). Pan-Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells. Angewandte Chemie International Edition (English), 50(25), 5734–5736.CrossRefGoogle Scholar
  90. 90.
    Kishigami, S., & Mishina, Y. (2005). BMP signaling and early embryonic patterning. Cytokine and Growth Factor Reviews, 16(3), 265–278.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Xu, R.-H., Chen, X., Li, D. S., Li, R., Addicks, G. C., Glennon, C., et al. (2002). BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nature Biotechnology, 20(12), 1261–1264.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Zhang, P., Li, J., Tan, Z., Wang, C., Liu, T., Chen, L., et al. (2008). Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood, 111(4), 1933–1941.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Richter, A., Valdimarsdottir, L., Hrafnkelsdottir, H. E., Runarsson, J. F., Omarsdottir, A. R., Oostwaard, D. W., et al. (2014). BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem Cells, 32(3), 636–648.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Chen, J. J., Liu, H., Liu, J., Qi, J., Wei, B., Yang, J., et al. (2012). H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nature Genetics, 45(1), 34.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Hamasaki, M., Hashizume, Y., Yamada, Y., Katayama, T., Hohjoh, H., Fusaki, N., et al. (2012). Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: Mechanisms of reprogramming and strategy for drug identification. Stem Cells, 30(11), 2437–2449.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Hayashi, Y., Hsiao, E. C., Sami, S., Lancero, M., Schlieve, C. R., Nguyen, T., et al. (2016). BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence. Proceedings of the National Academy of Sciences USA, 113(46), 13057–13062.CrossRefGoogle Scholar
  97. 97.
    Lin, L., Liang, L., Yang, X., Sun, H., Li, Y., Pei, D., & Zheng, H. (2018). The homeobox transcription factor MSX2 partially mediates the effects of bone morphogenetic protein 4 (BMP4) on somatic cell reprogramming. Journal of Biological Chemistry, 293(38), 14905–14915.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Utikal, J., Polo, J. M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R. M., et al. (2009). Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature, 460(7259), 1145–1148.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Collado, M., Blasco, M. A., & Serrano, M. (2007). Cellular senescence in cancer and aging. Cell, 130(2), 223–233.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Marion, R. M., Strati, K., Li, H., Tejera, A., Schoeftner, S., Ortega, S., et al. (2009). Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell, 4(2), 141–154.PubMedCrossRefGoogle Scholar
  101. 101.
    Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., et al. (2009). Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature, 460(7259), 1140–1144.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., et al. (2009). Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature, 460(7259), 1132–1135.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Banito, A., Rashid, S. T., Acosta, J. C., De Li, S., Pereira, C. F., Geti, I., et al. (2009). Senescence impairs successful reprogramming to pluripotent stem cells. Genes and Development, 23(18), 2134–2139.PubMedCrossRefGoogle Scholar
  104. 104.
    Jiang, J., Lv, W., Ye, X., Wang, L., Zhang, M., Yang, H., et al. (2012). Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Research, 23(1), 92–106.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Marión, R. M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., et al. (2009). A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature, 460(7259), 1149–1153.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., et al. (2008). Two supporting factors greatly improve the efficiency of human iPSC generation. Stem Cells, 3(5), 475–479.Google Scholar
  107. 107.
    Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Cãamero, M., et al. (2009). The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature, 460(7259), 1136–1139.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Sarig, R., Rivlin, N., Brosh, R., Bornstein, C., Kamer, I., Ezra, O., et al. (2010). Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells. Journal of Experimental Medicine, 207(10), 2127–2140.PubMedCrossRefGoogle Scholar
  109. 109.
    Horikawa, I., Park, K. Y., Isogaya, K., Hiyoshi, Y., Li, H., Anami, K., et al. (2017). Δ133P53 represses P53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells. Cell Death and Differentiation, 24(6), 1017–1028.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Hanna, J., Saha, K., Pando, B., Van Zon, J., Lengner, C. J., Creyghton, M. P., et al. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature, 462(7273), 595–601.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Yoshihara, M., Hayashizaki, Y., & Murakawa, Y. (2017). Genomic instability of iPSCs: Challenges towards their clinical applications. Stem Cell Reviews and Reports, 13(1), 7–16.CrossRefGoogle Scholar
  112. 112.
    Attwood, S., & Edel, M. (2019). iPS-cell technology and the problem of genetic instability—Can it ever be safe for clinical use? Journal of Clinical Medicine, 8(3), 288.PubMedCentralCrossRefPubMedGoogle Scholar
  113. 113.
    Abdelalim, E. M., & Tooyama, I. (2012). The p53 inhibitor, pifithrin-α, suppresses self-renewal of embryonic stem cells. Biochemical and Biophysical Research Communications, 420(3), 605–610.PubMedCrossRefGoogle Scholar
  114. 114.
    Zalzman, M., Falco, G., Sharova, L. V., Nishiyama, A., Thomas, M., Lee, S. L., et al. (2010). Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature, 464(7290), 858–863.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Skamagki, M., Correia, C., Yeung, P., Baslan, T., Beck, S., Zhang, C., et al. (2017). ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors. Nature Cell Biology, 19(9), 1037.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Aasen, T., Raya, A., Barrero, M. J., Garreta, E., Consiglio, A., Gonzalez, F., et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotechnology, 26(11), 1276–1284.PubMedCrossRefGoogle Scholar
  117. 117.
    Tüfekci, K. U., Öner, M. G., Meuwissen, R. L. J., & Genç, Ş. (2014). The role of MicroRNAs in human diseases BT. In M. Yousef & J. Allmer (Eds.), miRNomics: MicroRNA biology and computational analysis (pp. 33–50). Totowa: Humana Press.CrossRefGoogle Scholar
  118. 118.
    Zeng, Z.-L., Lin, X., Tan, L.-L., Liu, Y.-M., Qu, K., & Wang, Z. (2018). MicroRNAs: Important regulators of induced pluripotent stem cell generation and differentiation. Stem Cell Reviews and Reports, 14(1), 71–81.CrossRefGoogle Scholar
  119. 119.
    Wang, Y., Medvid, R., Melton, C., Jaenisch, R., & Blelloch, R. (2007). DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genetics, 39(3), 380–385.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kanellopoulou, C., Muljo, S. A., Kung, A. L., Ganesan, S., Drapkin, R., Jenuwein, T., et al. (2005). Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes and Development, 19(4), 489–501.PubMedCrossRefGoogle Scholar
  121. 121.
    Murchison, E. P., Partridge, J. F., Tam, O. H., Cheloufi, S., & Hannon, G. J. (2005). Characterization of Dicer-deficient murine embryonic stem cells. Proceedings of the National Academy of Sciences USA, 102(34), 12135–12140.CrossRefGoogle Scholar
  122. 122.
    Anokye-Danso, F., Trivedi, C. M., Juhr, D., Gupta, M., Cui, Z., Tian, Y., et al. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8(4), 376–388.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D. L., Kano, Y., et al. (2011). Reprogramming of mouse and human cells to pluripotency using mature MicroRNAs. Cell Stem Cell, 8(6), 633–638.PubMedCrossRefGoogle Scholar
  124. 124.
    Judson, R. L., Greve, T. S., Parchem, R. J., & Blelloch, R. (2013). MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells. Nature Structural and Molecular Biology, 20(10), 1227–1237.PubMedCrossRefGoogle Scholar
  125. 125.
    Pfaff, N., Fiedler, J., Holzmann, A., Schambach, A., Moritz, T., Cantz, T., & Thum, T. (2011). miRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2. EMBO reports, 12(11), 1153–1159.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Choi, Y. J., Lin, C., Ho, J. J., He, X., Okada, N., Bu, P., et al. (2011). miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nature Cell Biology, 13(11), 1353–1360.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    He, X., He, L., & Hannon, G. J. (2007). The guardian’s little helper: MicroRNAs in the p53 tumor suppressor network. Cancer Research, 67(23), 11099–11101.PubMedCrossRefGoogle Scholar
  128. 128.
    Lee, Y. L., Peng, Q., Fong, S. W., Chen, A. C. H., Lee, K. F., Ng, E. H. Y., et al. (2012). Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. PLOS ONE, 7(9), e45633.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Melton, C., Judson, R. L., & Blelloch, R. (2010). Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature, 463(7281), 621–626.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Marson, A., Levine, S. S., Cole, M. F., Frampton, G. M., Brambrink, T., Johnstone, S., et al. (2008). Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell, 134(3), 521–533.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Worringer, K. A., Rand, T. A., Hayashi, Y., Sami, S., Takahashi, K., Tanabe, K., et al. (2014). The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell Stem Cell, 14(1), 40–52.PubMedCrossRefGoogle Scholar
  132. 132.
    Yang, C. S., Li, Z., & Rana, T. M. (2011). microRNAs modulate iPS cell generation. RNA, 17(8), 1451–1460.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Park, S. Y., Lee, J. H., Ha, M., Nam, J. W., & Kim, V. N. (2009). miR-29 miRNAs activate p53 by targeting p85α and CDC42. Nature Structural and Molecular Biology, 16(1), 23–29.PubMedCrossRefGoogle Scholar
  134. 134.
    Li, Z., Dang, J., Chang, K. Y., & Rana, T. M. (2014). MicroRNA-mediated regulation of extracellular matrix formation modulates Somatic cell reprogramming. RNA, 20(12), 1900–1915.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wang, J., He, Q., Han, C., Gu, H., Jin, L., Li, Q., et al. (2012). P53-facilitated Mir-199a-3P regulates somatic cell reprogramming. Stem Cells, 30(7), 1405–1413.PubMedCrossRefGoogle Scholar
  136. 136.
    Pfaff, N., Liebhaber, S., Möbus, S., Beh-Pajooh, A., Fiedler, J., Pfanne, A., et al. (2017). Inhibition of miRNA-212/132 improves the reprogramming of fibroblasts into induced pluripotent stem cells by de-repressing important epigenetic remodelling factors. Stem Cell Research, 20, 70–75.PubMedCrossRefGoogle Scholar
  137. 137.
    Zhang, L., Zheng, Y., Sun, Y., Zhang, Y., Yan, J., Chen, Z., & Jiang, H. (2016). MiR-134-Mbd3 axis regulates the induction of pluripotency. Journal of Cellular and Molecular Medicine, 20(6), 1150–1158.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Hysolli, E., Tanaka, Y., Su, J., Kim, K. Y., Zhong, T., Janknecht, R., et al. (2016). Regulation of the DNA methylation landscape in human somatic cell reprogramming by the miR-29 family. Stem Cell Reports, 7(1), 43–54.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Xu, N., Papagiannakopoulos, T., Pan, G., Thomson, J. A., & Kosik, K. S. (2009). MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell, 137(4), 647–658.PubMedCrossRefGoogle Scholar
  140. 140.
    Barta, T., Peskova, L., Collin, J., Montaner, D., Neganova, I., Armstrong, L., & Lako, M. (2016). Brief report: Inhibition of miR-145 enhances reprogramming of human dermal fibroblasts to induced pluripotent stem cells. Stem Cells, 34(1), 246–251.Google Scholar
  141. 141.
    Weinhold, B. (2006). Epigenetics: The science of change, A160–A167.Google Scholar
  142. 142.
    Armstrong, L. (2012). Epigenetic control of embryonic stem cell differentiation. Stem Cell Reviews and Reports, 8(1), 67–77.CrossRefGoogle Scholar
  143. 143.
    Gonzalez, M., & Li, F. (2012). DNA replication, RNAi and epigenetic inheritance. Epigenetics, 7(1), 14–19.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Hochedlinger, K., & Jaenisch, R. (2015). Induced pluripotency and epigenetic reprogramming. Cold Spring Harbor Perspectives in Biology, 7(12), a019448.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Li, E., Bestor, T. H., & Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell, 69(6), 915–926.PubMedCrossRefGoogle Scholar
  146. 146.
    Okano, M., Bell, D. W., Haber, D. A., & Li, E. (1999). DNA Methyltransferases Dnmt3a and Dnmt3b are essential for De Novo methylation and mammalian development. Cell, 99(3), 247–257.PubMedCrossRefGoogle Scholar
  147. 147.
    Mali, P., Chou, B. K., Yen, J., Ye, Z., Zou, J., Dowey, S., et al. (2010). Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells, 28(4), 713–720.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Pasha, Z., Haider, H. K., & Ashraf, M. (2011). Efficient non-viral reprogramming of myoblasts to stemness with a single small molecule to generate cardiac progenitor cells. PLOS ONE, 6(8), e23667–e23667.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Epsztejn-Litman, S., Feldman, N., Abu-Remaileh, M., Shufaro, Y., Gerson, A., Ueda, J., et al. (2008). De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nature Structural & Molecular Biology, 15(11), 1176.CrossRefGoogle Scholar
  150. 150.
    Li, D., Guo, B., Wu, H., Tan, L., & Lu, Q. (2015). TET family of dioxygenases: Crucial roles and underlying mechanisms. Cytogenetic and Genome Research, 146(3), 171–180.PubMedCrossRefGoogle Scholar
  151. 151.
    Gao, Y., Chen, J., Li, K., Wu, T., Huang, B., Liu, W., et al. (2013). Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell, 12(4), 453–469.PubMedCrossRefGoogle Scholar
  152. 152.
    Hu, X., Zhang, L., Mao, S. Q., Li, Z., Chen, J., Zhang, R. R., et al. (2014). Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell, 14(4), 512–522.PubMedCrossRefGoogle Scholar
  153. 153.
    Costa, Y., Ding, J., Theunissen, T. W., Faiola, F., Hore, T. A., Shliaha, P. V., et al. (2013). NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature, 495(7441), 370–374.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Doege, C. A., Inoue, K., Yamashita, T., Rhee, D. B., Travis, S., Fujita, R., et al. (2012). Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature, 488(7413), 652–655.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Sardina, J. L., Collombet, S., Tian, T. V., Gómez, A., Di Stefano, B., Berenguer, C., et al. (2018). Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell, 23(5), 727–741.PubMedCrossRefGoogle Scholar
  156. 156.
    Esteban, M. A., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., et al. (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell, 6(1), 71–79.PubMedCrossRefGoogle Scholar
  157. 157.
    Chung, T., Brena, R. M., Kolle, G., Grimmond, S. M., Berman, B. P., Laird, P. W., et al. (2010). Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cells, 28(10), 1848–1855.PubMedCrossRefGoogle Scholar
  158. 158.
    Gao, Y., Han, Z., Li, Q., Wu, Y., Shi, X., Ai, Z., et al. (2015). Vitamin C induces a pluripotent state in mouse embryonic stem cells by modulating micro RNA expression. The FEBS journal, 282(4), 685–699.PubMedCrossRefGoogle Scholar
  159. 159.
    Blaschke, K., Ebata, K. T., Karimi, M. M., Zepeda-Martínez, J. A., Goyal, P., Mahapatra, S., et al. (2013). Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature, 500(7461), 222–226.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Chen, J., Guo, L., Zhang, L., Wu, H., Yang, J., Liu, H., et al. (2013). Vitamin C modulates TET1 function during somatic cell reprogramming. Nature Genetics, 45(12), 1504.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Bhutani, N., Brady, J. J., Damian, M., Sacco, A., Corbel, S. Y., & Blau, H. M. (2010). Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature, 463(7284), 1042–1047.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Morgan, H. D., Dean, W., Coker, H. A., Reik, W., & Petersen-Mahrt, S. K. (2004). Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: Implications for epigenetic reprogramming. Journal of Biological Chemistry, 279(50), 52353–52360.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D., & Grewal, S. I. S. (2001). Role of histone H3 Lysine 9 methylation in epigenetic control of heterochromatin assembly. Science, 292(2001), 110–113.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Feldman, N., Gerson, A., Fang, J., Li, E., Zhang, Y., Shinkai, Y., et al. (2006). G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nature Cell Biology, 8(2), 188–194.PubMedCrossRefGoogle Scholar
  165. 165.
    Onder, T. T., Kara, N., Cherry, A., Sinha, A. U., Zhu, N., Bernt, K. M., et al. (2012). Chromatin-modifying enzymes as modulators of reprogramming. Nature, 483(7391), 598–602.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Soufi, A., Donahue, G., & Zaret, K. S. (2012). Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell, 151(5), 994–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Sridharan, R., Gonzales-Cope, M., Chronis, C., Bonora, G., McKee, R., Huang, C., et al. (2013). Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1γ in reprogramming to pluripotency. Nature Cell Biology, 15(7), 872–882.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Cheloufi, S., Elling, U., Hopfgartner, B., Jung, Y. L., Murn, J., Ninova, M., et al. (2015). The histone chaperone CAF-1 safeguards somatic cell identity. Nature, 528(7581), 218–224.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Lachner, M., O’Carroll, D., Rea, S., Mechtler, K., & Jenuwein, T. (2001). Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature, 410(6824), 116–120.PubMedCrossRefGoogle Scholar
  170. 170.
    Zhu, J., Adli, M., Zou, J. Y., Verstappen, G., Coyne, M., Zhang, X., et al. (2013). Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell, 152(3), 642–654.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Sridharan, R., Gonzales-Cope, M., Chronis, C., Bonora, G., McKee, R., Huang, C., et al. (2013). Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1γ in reprogramming to pluripotency. Nature Cell Biology, 15(7), 872–882.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G., & Rauscher, F. J. (2002). SETDB1: A novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes and Development, 16(8), 919–932.PubMedCrossRefGoogle Scholar
  173. 173.
    Miles, D. C., de Vries, N. A., Gisler, S., Lieftink, C., Akhtar, W., Gogola, E., et al. (2017). TRIM28 is an epigenetic barrier to induced pluripotent stem cell reprogramming. Stem Cells, 35(1), 147–157.PubMedCrossRefGoogle Scholar
  174. 174.
    Wang, Q., Xu, X., Li, J., Liu, J., Gu, H., Zhang, R., et al. (2011). Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. Cell Research, 21(10), 1424.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Cacchiarelli, D., Trapnell, C., Ziller, M. J., Soumillon, M., Cesana, M., Karnik, R., et al. (2015). Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency. Cell, 162(2), 412–424.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Sun, H., Liang, L., Li, Y., Feng, C., Li, L., Zhang, Y., et al. (2016). Lysine-specific histone demethylase 1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch. Scientific Reports, 6, 30903.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Wang, T., Chen, K., Zeng, X., Yang, J., Wu, Y., Shi, X., et al. (2011). The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell, 9(6), 575–587.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Liao, B., Bao, X., Liu, L., Feng, S., Zovoilis, A., Liu, W., et al. (2011). MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. Journal of Biological Chemistry, 286(19), 17359–17364.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    He, J., Kallin, E. M., Tsukada, Y. I., & Zhang, Y. (2008). The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b. Nature Structural and Molecular Biology, 15(11), 1169–1175.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Tzatsos, A., Pfau, R., Kampranis, S. C., & Tsichlis, P. N. (2009). Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the lnk4a/Arf locus. Proceedings of the National Academy of Sciences USA, 106(8), 2641–2646. Scholar
  181. 181.
    Liang, G., He, J., & Zhang, Y. (2012). Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nature Cell Biology, 14(5), 457–466.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Jones, B., Su, H., Bhat, A., Lei, H., Bajko, J., Hevi, S., et al. (2008). The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLOS Genetics, 4(9), e1000190.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Ng, H. H., Ciccone, D. N., Morshead, K. B., Oettinger, M. A., & Struhl, K. (2003). Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: A potential mechanism for position-effect variegation. Proceedings of the National Academy of Sciences USA, 100(4), 1820–1825.CrossRefGoogle Scholar
  184. 184.
    Wood, K., Tellier, M., & Murphy, S. (2018). DOT1L and H3K79 methylation in transcription and genomic stability. Biomolecules, 8(1), 11.PubMedCentralCrossRefGoogle Scholar
  185. 185.
    Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., et al. (2012). The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature, 488(7411), 409–413.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Gaspar-Maia, A., Qadeer, Z. A., Hasson, D., Ratnakumar, K., Adrian Leu, N., Leroy, G., et al. (2013). MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nature Communications, 4, 1512–1565.CrossRefGoogle Scholar
  187. 187.
    Pasque, V., Radzisheuskaya, A., Gillich, A., Halley-Stott, R. P., Panamarova, M., Zernicka-Goetz, M., et al. (2012). Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. Journal of Cell Science, 125(24), 6094–6104.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Barrero, M. J., Sese, B., Kuebler, B., Bilic, J., Boue, S., Martí, M., & Izpisua Belmonte, J. C. (2013). Macrohistone variants preserve cell identity by preventing the gain of H3K4me2 during reprogramming to pluripotency. Cell Reports, 3(4), 1005–1011.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Seto, E., & Yoshida, M. (2014). Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harbor Perspectives in Biology, 6(4), 1–26.CrossRefGoogle Scholar
  190. 190.
    Kretsovali, A., Hadjimichael, C., & Charmpilas, N. (2012). Histone deacetylase inhibitors in cell pluripotency, differentiation, and reprogramming. Stem Cells International, 2012, 1–10.CrossRefGoogle Scholar
  191. 191.
    Shahbazian, M. D., & Grunstein, M. (2007). Functions of site-specific histone acetylation and deacetylation. Annual Review of Biochemistry, 76(1), 75–100.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Huynh, N. C.-N., Everts, V., & Ampornaramveth, R. S. (2017). Histone deacetylases and their roles in mineralized tissue regeneration. Bone Reports, 7, 33–40.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., et al. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26(11), 1269–1275.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Liang, G., Taranova, O., Xia, K., & Zhang, Y. (2010). Butyrate promotes induced pluripotent stem cell generation. Journal of Biological Chemistry, 285(33), 25516–25521.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Pandian, G. N., Sato, S., Anandhakumar, C., Taniguchi, J., Takashima, K., Syed, J., et al. (2014). Identification of a small molecule that turns on the pluripotency gene circuitry in human fibroblasts. ACS Chemical Biology, 9(12), 2729–2736.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Zhang, Z., & Wu, W. S. (2013). Sodium butyrate promotes generation of human induced pluripotent stem cells through induction of the miR302/367 cluster. Stem Cells and Development, 22(16), 2268–2277.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Wei, T., Chen, W., Wang, X., Zhang, M., Chen, J., Zhu, S., et al. (2015). An HDAC2-TET1 switch at distinct chromatin regions significantly promotes the maturation of pre-iPS to iPS cells. Nucleic Acids Research, 43(11), 5409–5422.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Zhai, Y., Chen, X., Yu, D., Li, T., Cui, J., Wang, G., et al. (2015). Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress. Experimental Cell Research, 337(1), 61–67.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Saunders, A., Huang, X., Fidalgo, M., Reimer, M. H., Faiola, F., Ding, J., et al. (2017). The SIN3A/HDAC corepressor complex functionally cooperates with NANOG to promote pluripotency. Cell Reports, 18(7), 1713–1726.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Pasque, V., Gillich, A., Garrett, N., & Gurdon, J. B. (2011). Histone variant macroH2A confers resistance to nuclear reprogramming. The EMBO Journal, 30(12), 2373–2387.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Pliatska, M., Kapasa, M., Kokkalis, A., Polyzos, A., & Thanos, D. (2018). The histone variant macroH2A blocks cellular reprogramming by inhibiting mesenchymal-to-epithelial transition. Molecular and Cellular Biology, 38(10), e00669–e00617.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Fang, H. T., El Farran, C. A., Xing, Q. R., Zhang, L. F., Li, H., Lim, B., & Loh, Y. H. (2018). Global H3.3 dynamic deposition defines its bimodal role in cell fate transition. Nature Communications, 9(1), 1537.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Jang, C. W., Shibata, Y., Starmer, J., Yee, D., & Magnuson, T. (2015). Histone H3.3 maintains genome integrity during mammalian development. Genes and Development, 29(13), 1377–1393.PubMedCrossRefGoogle Scholar
  204. 204.
    Denslow, S. A., & Wade, P. A. (2007). The human Mi-2/NuRD complex and gene regulation. Oncogene, 26(37), 5433–5438.PubMedCrossRefGoogle Scholar
  205. 205.
    Le Guezennec, X., Vermeulen, M., Brinkman, A. B., Hoeijmakers, W. A. M., Cohen, A., Lasonder, E., & Stunnenberg, H. G. (2006). MBD2 / NuRD and MBD3 / NuRD, two distinct complexes with different biochemical and functional properties. Molecular and Cellular Biology, 26(3), 843–851.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Menafra, R., & Stunnenberg, H. G. (2014). MBD2 and MBD3: Elusive functions and mechanisms. Frontiers in Genetics, 5, 428.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Luo, M., Ling, T., Xie, W., Sun, H., Zhou, Y., Zhu, Q., et al. (2013). NuRD blocks reprogramming of mouse somatic cells into Pluripotent stem cells. Stem Cells, 31(7), 1278–1286.PubMedCrossRefGoogle Scholar
  208. 208.
    Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., et al. (2013). Deterministic direct reprogramming of somatic cells to pluripotency. Nature, 502(7469), 65–70.PubMedCrossRefGoogle Scholar
  209. 209.
    Zviran, A., Rais, Y., Mor, N., Novershtern, N., & Hanna, J. (2015). Mbd3/NuRD is a key inhibitory module during the induction and maintenance of naïve pluripotency. bioRxiv, 013961.Google Scholar
  210. 210.
    Dos Santos, R. L., Tosti, L., Radzisheuskaya, A., Caballero, I. M., Kaji, K., Hendrich, B., & Silva, J. C. R. (2014). MBD3/NuRD facilitates induction of pluripotency in a context-dependent manner. Cell Stem Cell, 15(1), 102–110.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Lee, M. R., Prasain, N., Chae, H. D., Kim, Y. J., Mantel, C., Yoder, M. C., & Broxmeyer, H. E. (2013). Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem Cells, 31(4), 666–681.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Lu, Y., Loh, Y. H., Li, H., Cesana, M., Ficarro, S. B., Parikh, J. R., et al. (2014). Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell, 15(1), 92–101.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Zhang, W., Feng, G., Wang, L., Teng, F., Wang, L., Li, W., et al. (2018). MeCP2 deficiency promotes cell reprogramming by stimulating IGF1/AKT/mTOR signaling and activating ribosomal protein-mediated cell cycle gene translation. Journal of Molecular Cell Biology, 10(6), 515–526.PubMedCrossRefGoogle Scholar
  214. 214.
    Jones, P. L., Veenstra, G. C. J., Wade, P. A., Vermaak, D., Kass, S. U., Landsberger, N., et al. (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genetics, 19(2), 187.PubMedCrossRefGoogle Scholar
  215. 215.
    Takami, Y., Ono, T., Fukagawa, T., Shibahara, K., & Nakayama, T. (2007). Essential role of chromatin assembly factor-1-mediated rapid nucleosome assembly for DNA replication and cell division in vertebrate cells. Molecular Biology of the Cell, 18(1), 129–141.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Sauer, P. V, Gu, Y., Liu, W. H., Mattiroli, F., Panne, D., Luger, K., & Churchill, M. E. (2018). Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor-1. Nucleic Acids Research, 46(19), 9907–9917.Google Scholar
  217. 217.
    Houlard, M., Berlivet, S., Probst, A. V., Quivy, J. P., Héry, P., Almouzni, G., & Gérard, M. (2006). CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells. PLOS Genetics, 2(11), 1686–1696.CrossRefGoogle Scholar
  218. 218.
    Chen, J., Liu, H., Liu, J., Qi, J., Wei, B., Yang, J., et al. (2013). H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nature Genetics, 45(1), 34–42.PubMedCrossRefGoogle Scholar
  219. 219.
    Kolundzic, E., Ofenbauer, A., Bulut, S. I., Uyar, B., Baytek, G., Sommermeier, A., et al. (2018). FACT sets a barrier for cell fate reprogramming in caenorhabditis elegans and human cells. Developmental Cell, 46(5), 611–626.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Orphanides, G., LeRoy, G., Chang, C.-H., Luse, D. S., & Reinberg, D. (1998). FACT, a factor that facilitates transcript elongation through nucleosomes. Cell, 92(1), 105–116.PubMedCrossRefGoogle Scholar
  221. 221.
    Li, W., Chen, P., Yu, J., Dong, L., Liang, D., Feng, J., et al. (2016). FACT remodels the tetranucleosomal unit of chromatin fibers for gene transcription. Molecular Cell, 64(1), 120–133.PubMedCrossRefGoogle Scholar
  222. 222.
    Yang, J., Zhang, X., Feng, J., Leng, H., Li, S., Xiao, J., et al. (2016). The histone chaperone FACT contributes to dna replication-coupled nucleosome assembly. Cell Reports, 14(5), 1128–1141.PubMedCrossRefGoogle Scholar
  223. 223.
    Chen, P., Dong, L., Hu, M., Wang, Y. Z., Xiao, X., Zhao, Z., et al. (2018). Functions of FACT in breaking the nucleosome and maintaining its integrity at the single-nucleosome level. Molecular Cell, 71(2), 284–293.PubMedCrossRefGoogle Scholar
  224. 224.
    Yang, C., Lopez, C. G., & Rana, T. M. (2011). Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation. Stem Cells, 29(10), 1528–1536.PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Borkent, M., Bennett, B. D., Lackford, B., Bar-Nur, O., Brumbaugh, J., Wang, L., et al. (2016). A serial shRNA screen for roadblocks to reprogramming identifies the protein modifier SUMO2. Stem Cell Reports, 6(5), 704–716.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Duffy, M. J., Mullooly, M., O’Donovan, N., Sukor, S., Crown, J., Pierce, A., & McGowan, P. M. (2011). The ADAMs family of proteases: New biomarkers and therapeutic targets for cancer? Clinical Proteomics, 8(1), 1–13.CrossRefGoogle Scholar
  227. 227.
    Edwards, D. R., Handsley, M. M., & Pennington, C. J. (2009). The ADAM metalloproteinases. Molecular Aspects of Medicine, 29(5), 258–289.CrossRefGoogle Scholar
  228. 228.
    Scita, G., & Di Fiore, P. P. (2010). The endocytic matrix. Nature, 463(7280), 464–473.PubMedCrossRefGoogle Scholar
  229. 229.
    Watanabe, S., & Boucrot, E. (2017). Fast and ultrafast endocytosis. Current Opinion in Cell Biology, 47, 64–71.PubMedCrossRefGoogle Scholar
  230. 230.
    Doherty, G. J., & McMahon, H. T. (2009). Mechanisms of endocytosis. Annual Review of Biochemistry, 78(1), 857–902.PubMedCrossRefGoogle Scholar
  231. 231.
    McMahon, H. T., & Boucrot, E. (2011). Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nature Reviews Molecular Cell Biology, 12(8), 517–533.PubMedCrossRefGoogle Scholar
  232. 232.
    Di Guglielmo, G. M., Le Roy, C., Goodfellow, A. F., & Wrana, J. L. (2003). Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nature Cell Biology, 5(5), 410.PubMedCrossRefGoogle Scholar
  233. 233.
    Reits, E. A. J., Benham, A. M., Plougastel, B., Neefjes, J., & Trowsdale, J. (1997). Dynamics of proteasome distribution in living cells. The EMBO journal, 16(20), 6087–6094.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Pickart, C. M. (2001). Mechanisms underlying ubiquitination. Annual Review of Biochemistry, 70(1), 503–533.PubMedCrossRefGoogle Scholar
  235. 235.
    Tu, Y., Chen, C., Pan, J., Xu, J., Zhou, Z.-G. G., & Wang, C.-Y. Y. (2012). The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis. International Journal of Clinical and Experimental Pathology, 5(8), 726–738.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Okita, Y., & Nakayama, K. I. (2012). UPS delivers pluripotency. Cell Stem Cell, 11(6), 728–730.PubMedCrossRefGoogle Scholar
  237. 237.
    Szutorisz, H., Georgiou, A., Tora, L., & Dillon, N. (2006). The proteasome restricts permissive transcription at tissue-specific gene loci in embryonic stem cells. Cell, 127(7), 1375–1388.PubMedCrossRefGoogle Scholar
  238. 238.
    Liao, B., & Jin, Y. (2010). Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner. Cell Research, 20(3), 332.PubMedCrossRefGoogle Scholar
  239. 239.
    Ramakrishna, S., Suresh, B., Lim, K.-H., Cha, B.-H., Lee, S.-H., Kim, K.-S., & Baek, K.-H. (2011). PEST motif sequence regulating human NANOG for proteasomal degradation. Stem Cells and Development, 20(9), 1511–1519.PubMedCrossRefGoogle Scholar
  240. 240.
    Buckley, S. M., Aranda-Orgilles, B., Strikoudis, A., Apostolou, E., Loizou, E., Moran-Crusio, K., et al. (2012). Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell, 11(6), 783–798.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Lu, D., Davis, M. P. A., Abreu-Goodger, C., Wang, W., Campos, L. S., Siede, J., et al. (2012). MiR-25 regulates Wwp2 and Fbxw7 and promotes reprogramming of mouse fibroblast cells to iPSCs. PLOS ONE, 7(8), e40938.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Xu, H. M., Liao, B., Zhang, Q. J., Wang, B. B., Li, H., Zhong, X. M., et al. (2004). Wwp2, An E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. Journal of Biological Chemistry, 279(22), 23495–23503.PubMedCrossRefGoogle Scholar
  243. 243.
    Welcker, M., Orian, A., Grim, J. A., Eisenman, R. N., & Clurman, B. E. (2004). A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Current Biology, 14(20), 1852–1857.PubMedCrossRefGoogle Scholar
  244. 244.
    Liu, N., Li, H., Li, S., Shen, M., Xiao, N., Chen, Y., et al. (2010). The Fbw7/human CDC4 tumor suppressor targets proproliferative factor KLF5 for ubiquitination and degradation through multiple phosphodegron motifs. Journal of Biological Chemistry, 285(24), 18858–18867.PubMedCrossRefGoogle Scholar
  245. 245.
    Hay, R. T. (2005). SUMO: A history of modification. Molecular Cell, 18(1), 1–12.PubMedCrossRefGoogle Scholar
  246. 246.
    Tahmasebi, S., Ghorbani, M., Savage, P., Gocevski, G., & Yang, X. J. (2014). The SUMO conjugating enzyme Ubc9 is required for inducing and maintaining stem cell pluripotency. Stem Cells, 32(4), 1012–1020.PubMedCrossRefGoogle Scholar
  247. 247.
    Liao, J., Marumoto, T., Yamaguchi, S., Okano, S., Takeda, N., Sakamoto, C., et al. (2013). Inhibition of PTEN tumor suppressor promotes the generation of induced pluripotent stem cells. Molecular Therapy, 21(6), 1242–1250.PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    Yang, C. S., Chang, K. Y., & Rana, T. M. (2014). Genome-wide functional analysis reveals factors needed at the transition steps of induced reprogramming. Cell Reports, 8(2), 327–337.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and BioengineeringIndian Institute of Technology GuwahatiGuwahatiIndia

Personalised recommendations