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Progress in understanding epigenetic remodeling during induced pluripotency

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  • Life & Medical Sciences
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Science Bulletin

Abstract

Over 50 years of efforts, cellular reprogramming opens a new door for disease modeling and regenerative medicine. Although induction of pluripotency by transcription factors has become common, only a small portion of basic mechanisms of epigenetic modifications during this process have been revealed. To clearly understand reprogramming and devise ways to promote full transition towards pluripotency, we must gain insight from comprehensive characterizations of cells at distinct reprogramming stages, which involves gene expression profiling, chromatin state maps of key activating and repressive marks, and DNA modifications. Here, we review recent advances in epigenetic reprogramming to pluripotency with a focus on the principal molecular regulators and attach importance to the combination of high-throughput sequencing and systematic biology approaches in uncovering underlying molecular mechanisms of this unique platform in future researches.

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References

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

    Article  Google Scholar 

  2. Zhao XY, Li W, Lv Z et al (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90

    Article  Google Scholar 

  3. Boland MJ, Hazen JL, Nazor KL et al (2009) Adult mice generated from induced pluripotent stem cells. Nature 461:U91–U94

    Article  Google Scholar 

  4. Kang L, Wang J, Zhang Y et al (2009) iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5:135–138

    Article  Google Scholar 

  5. Soldner F, Hockemeyer D, Beard C et al (2009) Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–977

    Article  Google Scholar 

  6. Carvajal-Vergara X, Sevilla A, D'Souza SL et al (2010) Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465:808–812

    Article  Google Scholar 

  7. Raya A, Rodriguez-Piza I, Guenechea G et al (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59

    Article  Google Scholar 

  8. Lee G, Papapetrou EP, Kim H et al (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461:402–406

    Article  Google Scholar 

  9. Ebert AD, Yu J, Rose FF et al (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280

    Article  Google Scholar 

  10. Smith ZD, Nachman I, Regev A et al (2010) Dynamic single-cell imaging of direct reprogramming reveals an early specifying event. Nat Biotechnol 28:521–526

    Article  Google Scholar 

  11. Samavarchi-Tehrani P, Golipour A, David L et al (2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7:64–77

    Article  Google Scholar 

  12. Stadtfeld M, Maherali N, Breault DT et al (2008) Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2:230–240

    Article  Google Scholar 

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

    Article  Google Scholar 

  14. Brambrink T, Foreman R, Welstead GG et al (2008) Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2:151–159

    Article  Google Scholar 

  15. Buganim Y, Faddah DA, Cheng AW et al (2012) Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150:1209–1222

    Article  Google Scholar 

  16. Hanna J, Saha K, Pando B et al (2009) Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462:595–601

    Article  Google Scholar 

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

    Article  Google Scholar 

  18. Rais Y, Zviran A, Geula S et al (2013) Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502:65–70

    Article  Google Scholar 

  19. Le Guezennec X, Vermeulen M, Brinkman AB et al (2006) MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol 26:843–851

    Article  Google Scholar 

  20. Kaji K, Nichols J, Hendrich B (2007) Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134:1123–1132

    Article  Google Scholar 

  21. Guo S, Zi X, Schulz VP et al (2014) Nonstochastic reprogramming from a privileged somatic cell state. Cell 156:649–662

    Article  Google Scholar 

  22. Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128:635–638

    Article  Google Scholar 

  23. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  Google Scholar 

  24. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45

    Article  Google Scholar 

  25. Koche RP, Smith ZD, Adli M et al (2011) Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8:96–105

    Article  Google Scholar 

  26. Polo JM, Anderssen E, Walsh RM et al (2012) A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151:1617–1632

    Article  Google Scholar 

  27. Onder TT, Kara N, Cherry A et al (2012) Chromatin-modifying enzymes as modulators of reprogramming. Nature 483:598–602

    Article  Google Scholar 

  28. Mansour AA, Gafni O, Weinberger L et al (2012) The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 488:409–413

    Article  Google Scholar 

  29. Bulger M, Groudine M (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144:327–339

    Article  Google Scholar 

  30. Roeder RG (2005) Transcriptional regulation and the role of diverse coactivators in animal cells. FEBS Lett 579:909–915

    Article  Google Scholar 

  31. Rada-Iglesias A, Bajpai R, Swigut T et al (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470:279–283

    Article  Google Scholar 

  32. Creyghton MP, Cheng AW, Welstead GG et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107:21931–21936

    Article  Google Scholar 

  33. Heintzman ND, Hon GC, Hawkins RD et al (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:108–112

    Article  Google Scholar 

  34. Whyte WA, Bilodeau S, Orlando DA et al (2012) Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482:221–225

    Google Scholar 

  35. Lee JE, Wang CC, Xu SLY et al (2013) H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife 2:e01503

    Google Scholar 

  36. Chen J, Liu H, Liu J et al (2013) H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet 45:34–42

    Article  Google Scholar 

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

    Article  Google Scholar 

  38. Esteban MA, Wang T, Qin B et al (2010) Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6:71–79

    Article  Google Scholar 

  39. Huangfu D, Maehr R, Guo W et al (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26:795–797

    Article  Google Scholar 

  40. Huangfu D, Osafune K, Maehr R et al (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26:1269–1275

    Article  Google Scholar 

  41. Mali P, Chou BK, Yen J 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 28:713–720

    Article  Google Scholar 

  42. Liang G, Taranova O, Xia K et al (2010) Butyrate promotes induced pluripotent stem cell generation. J Biol Chem 285:25516–25521

    Article  Google Scholar 

  43. Zhang Z, Wu WS (2013) Sodium butyrate promotes generation of human induced pluripotent stem cells through induction of the miR302/367 cluster. Stem Cells Dev 22:2268–2277

    Article  Google Scholar 

  44. Tonge PD, Corso AJ, Monetti C et al (2014) Divergent reprogramming routes lead to alternative stem-cell states. Nature 516:192–197

    Article  Google Scholar 

  45. Hussein SM, Puri MC, Tonge PD et al (2014) Genome-wide characterization of the routes to pluripotency. Nature 516:198–206

    Article  Google Scholar 

  46. Yang PK, Kuroda MI (2007) Noncoding RNAs and intranuclear positioning in monoallelic gene expression. Cell 128:777–786

    Article  Google Scholar 

  47. Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452

    Article  Google Scholar 

  48. Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14:341–356

    Article  Google Scholar 

  49. Kim J, Woo AJ, Chu J et al (2010) A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143:313–324

    Article  Google Scholar 

  50. Sridharan R, Tchieu J, Mason MJ et al (2009) Role of the murine reprogramming factors in the induction of pluripotency. Cell 136:364–377

    Article  Google Scholar 

  51. Mikkelsen TS, Hanna J, Zhang X et al (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454:49–55

    Article  Google Scholar 

  52. Piccolo FM, Bagci H, Brown KE et al (2013) Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EGC fusion. Mol Cell 49:1023–1033

    Article  Google Scholar 

  53. Hu X, Zhang L, Mao SQ et al (2014) Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell 14:512–522

    Article  Google Scholar 

  54. Doege CA, Inoue K, Yamashita T et al (2012) Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488:652–655

    Article  Google Scholar 

  55. Costa Y, Ding J, Theunissen TW et al (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495:370–374

    Article  Google Scholar 

  56. Gao Y, Chen J, Li K 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 12:453–469

    Article  Google Scholar 

  57. Chen J, Gao Y, Huang H et al (2014) The combination of Tet1 with Oct4 generates high-quality mouse induced pluripotent stem cells (iPSCs). Stem Cells 33:686–698

    Article  Google Scholar 

  58. Jackson SA, Sridharan R (2013) The nexus of Tet1 and the pluripotency network. Cell Stem Cell 12:387–388

    Article  Google Scholar 

  59. Papp B, Plath K (2013) Epigenetics of reprogramming to induced pluripotency. Cell 152:1324–1343

    Article  Google Scholar 

  60. Maherali N, Sridharan R, Xie W et al (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1:55–70

    Article  Google Scholar 

  61. Han DW, Greber B, Wu G et al (2011) Direct reprogramming of fibroblasts into epiblast stem cells. Nat Cell Biol 13:66–71

    Article  Google Scholar 

  62. Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487–492

    Article  Google Scholar 

  63. Chen Q, Gao S, He W et al (2014) Xist repression shows time-dependent effects on the reprogramming of female somatic cells to induced pluripotent stem cells. Stem Cells 32:2642–2656

    Article  Google Scholar 

  64. Hoffman LM, Hall L, Batten JL et al (2005) X-inactivation status varies in human embryonic stem cell lines. Stem Cells 23:1468–1478

    Article  Google Scholar 

  65. Shen Y, Matsuno Y, Fouse SD et al (2008) X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci USA 105:4709–4714

    Article  Google Scholar 

  66. Silva SS, Rowntree RK, Mekhoubad S et al (2008) X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. Proc Natl Acad Sci USA 105:4820–4825

    Article  Google Scholar 

  67. Anguera MC, Sadreyev R, Zhang Z et al (2012) Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 11:75–90

    Article  Google Scholar 

  68. Mekhoubad S, Bock C, de Boer AS et al (2012) Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell 10:595–609

    Article  Google Scholar 

  69. Tomoda K, Takahashi K, Leung K et al (2012) Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 11:91–99

    Article  Google Scholar 

  70. Orkin SH, Hochedlinger K (2011) Chromatin connections to pluripotency and cellular reprogramming. Cell 145:835–850

    Article  Google Scholar 

  71. Skene PJ, Henikoff S (2013) Histone variants in pluripotency and disease. Development 140:2513–2524

    Article  Google Scholar 

  72. Shinagawa T, Takagi T, Tsukamoto D et al (2014) Histone variants enriched in oocytes enhance reprogramming to induced pluripotent stem cells. Cell Stem Cell 14:217–227

    Article  Google Scholar 

  73. Gaspar-Maia A, Qadeer ZA, Hasson D et al (2013) MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nat Commun 4:1565

    Article  Google Scholar 

  74. Buganim Y, Markoulaki S, van Wietmarschen N et al (2014) The developmental potential of iPSCs is greatly influenced by reprogramming factor selection. Cell Stem Cell 15:295–309

    Article  Google Scholar 

  75. Wu T, Liu Y, Wen D et al (2014) Histone variant H2A.X deposition pattern serves as a functional epigenetic mark for distinguishing the developmental potentials of iPSCs. Cell Stem Cell 15:281–294

    Article  Google Scholar 

  76. Gao Y, Gao S (2014) Quality control: H2A.X links to better iPSCs. Cell Stem Cell 15:259–260

    Article  Google Scholar 

  77. Kagey MH, Newman JJ, Bilodeau S et al (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467:430–435

    Article  Google Scholar 

  78. Schoenfelder S, Sexton T, Chakalova L et al (2010) Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat Genet 42:53–61

    Article  Google Scholar 

  79. Gaspar-Maia A, Alajem A, Meshorer E et al (2011) Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol 12:36–47

    Article  Google Scholar 

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

    Article  Google Scholar 

  81. Lieberman-Aiden E, van Berkum NL, Williams L et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–293

    Article  Google Scholar 

  82. Dixon JR, Selvaraj S, Yue F et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380

    Article  Google Scholar 

  83. de Wit E, Bouwman BA, Zhu Y et al (2013) The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature 501:227–231

    Article  Google Scholar 

  84. Apostolou E, Ferrari F, Walsh RM et al (2013) Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell Stem Cell 12:699–712

    Article  Google Scholar 

  85. Wei Z, Gao F, Kim S et al (2013) Klf4 organizes long-range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. Cell Stem Cell 13:36–47

    Article  Google Scholar 

  86. Sexton T, Cavalli G (2013) The 3D genome shapes up for pluripotency. Cell Stem Cell 13:3–4

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (31325019, 91319306 and 31401247) and Ministry of Science and Technology of China (2015CB964800 and 2014CB964601). We are grateful to our colleagues in the laboratory for their assistance with the preparation of this manuscript.

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The authors declare that they have no conflicts of interest.

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Correspondence to Shaorong Gao.

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SPECIAL TOPIC: Stem cell, Basis and Application

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Gao, R., Liu, X. & Gao, S. Progress in understanding epigenetic remodeling during induced pluripotency. Sci. Bull. 60, 1713–1721 (2015). https://doi.org/10.1007/s11434-015-0919-4

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  • DOI: https://doi.org/10.1007/s11434-015-0919-4

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