Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epigenetic modifications in pluripotent and differentiated cells

Nature Biotechnology volume 28, pages 1079–1088 (2010)Cite this article

Subjects

Abstract

Epigenetic modifications constitute a complex regulatory layer on top of the genome sequence. Pluripotent and differentiated cells provide a powerful system for investigating how the epigenetic code influences cellular fate. High-throughput sequencing of these cell types has yielded DNA methylation maps at single-nucleotide resolution and many genome-wide chromatin maps. In parallel to epigenome mapping efforts, remarkable progress has been made in our ability to manipulate cell states; ectopic expression of transcription factors has been shown to override developmentally established epigenetic marks and to enable routine generation of induced pluripotent stem (iPS) cells. Despite these advances, many fundamental questions remain. The roles of epigenetic marks and, in particular, of epigenetic modifiers in development and in disease states are not well understood. Although iPS cells appear molecularly and functionally similar to embryonic stem cells, more genome-wide studies are needed to define the extent and functions of epigenetic remodeling during reprogramming.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Epigenetic dynamics during in vitro and in vivo differentiation.
Figure 2: Epigenetic reprogramming during iPS cell derivation.

Similar content being viewed by others

References

  1. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

    CAS  PubMed  Google Scholar 

  2. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 Suppl, 245–254 (2003).

    CAS  PubMed  Google Scholar 

  3. Yamanaka, S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1, 39–49 (2007).

    CAS  PubMed  Google Scholar 

  4. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001).

    CAS  PubMed  Google Scholar 

  5. Rideout, W.M. III, Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).

    CAS  PubMed  Google Scholar 

  6. Hammoud, S.S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475–478 (2000).

    CAS  PubMed  Google Scholar 

  8. Santos, F., Hendrich, B., Reik, W. & Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172–182 (2002).

    CAS  PubMed  Google Scholar 

  9. Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000).

    CAS  PubMed  Google Scholar 

  10. Kafri, T. et al. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. Genes Dev. 6, 705–714 (1992).

    CAS  PubMed  Google Scholar 

  11. Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).

    CAS  PubMed  Google Scholar 

  12. Rossant, J. Stem cells and early lineage development. Cell 132, 527–531 (2008).

    CAS  PubMed  Google Scholar 

  13. Niakan, K.K. et al. Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev. 24, 312–326 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tanaka, S., Kunath, T., Hadjantonakis, A.K., Nagy, A. & Rossant, J. Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075 (1998).

    CAS  PubMed  Google Scholar 

  15. Evans, M.J. & Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).

    CAS  PubMed  Google Scholar 

  16. Martin, G.R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78, 7634–7638 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, A.E. et al. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell 4, 103–106 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cowan, C.A. et al. Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med. 350, 1353–1356 (2004).

    CAS  PubMed  Google Scholar 

  19. Thomson, J.A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  20. Silva, J. & Smith, A. Capturing pluripotency. Cell 132, 532–536 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat. Genet. 27, 31–39 (2001).

    CAS  PubMed  Google Scholar 

  23. Jones, P.A. & Baylin, S.B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Goll, M.G. & Bestor, T.H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).

    CAS  PubMed  Google Scholar 

  25. Okano, M., Xie, S. & Li, E. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 26, 2536–2540 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Goll, M.G. et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395–398 (2006).

    CAS  PubMed  Google Scholar 

  27. Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    CAS  PubMed  Google Scholar 

  28. Okano, M., Bell, D.W., Haber, D.A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    CAS  PubMed  Google Scholar 

  29. Dodge, J.E. et al. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J. Biol. Chem. 280, 17986–17991 (2005).

    CAS  PubMed  Google Scholar 

  30. Kaneda, M. et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429, 900–903 (2004).

    CAS  PubMed  Google Scholar 

  31. Bourc'his, D., Xu, G.L., Lin, C.S., Bollman, B. & Bestor, T.H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

    CAS  PubMed  Google Scholar 

  32. Bourc'his, D. & Bestor, T.H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004).

    CAS  PubMed  Google Scholar 

  33. Jia, D., Jurkowska, R.Z., Zhang, X., Jeltsch, A. & Cheng, X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449, 248–251 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ooi, S.K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hayashi, K. & Surani, M.A. Resetting the epigenome beyond pluripotency in the germline. Cell Stem Cell 4, 493–498 (2009).

    CAS  PubMed  Google Scholar 

  36. Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    CAS  PubMed  Google Scholar 

  38. Shi, Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat. Rev. Genet. 8, 829–833 (2007).

    CAS  PubMed  Google Scholar 

  39. Francis, N.J. & Kingston, R.E. Mechanisms of transcriptional memory. Nat. Rev. Mol. Cell Biol. 2, 409–421 (2001).

    CAS  PubMed  Google Scholar 

  40. Campos, E.I. & Reinberg, D. Histones: annotating chromatin. Annu. Rev. Genet. 43, 559–599 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    CAS  PubMed  Google Scholar 

  43. Zhang, Y., Cao, R., Wang, L. & Jones, R.S. Mechanism of Polycomb group gene silencing. Cold Spring Harb. Symp. Quant. Biol. 69, 309–317 (2004).

    CAS  PubMed  Google Scholar 

  44. Faust, C., Lawson, K.A., Schork, N.J., Thiel, B. & Magnuson, T. The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo. Development 125, 4495–4506 (1998).

    CAS  PubMed  Google Scholar 

  45. O'Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pasini, D., Bracken, A.P., Jensen, M.R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Shen, X. et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol. Cell 32,

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ezhkova, E. et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Shumacher, A., Faust, C. & Magnuson, T. Positional cloning of a global regulator of anterior-posterior patterning in mice. Nature 383, 250–253 (1996).

    CAS  PubMed  Google Scholar 

  50. Hanson, R.D. et al. Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. Proc. Natl. Acad. Sci. USA 96, 14372–14377 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. van der Lugt, N.M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).

    CAS  PubMed  Google Scholar 

  52. Dodge, J.E., Kang, Y.K., Beppu, H., Lei, H. & Li, E. Histone H3–K9 methyltransferase ESET is essential for early development. Mol. Cell. Biol. 24, 2478–2486 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3–K9. Genes Dev. 19, 815–826 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3, 662–673 (2002).

    CAS  PubMed  Google Scholar 

  55. Surani, M.A., Hayashi, K. & Hajkova, P. Genetic and epigenetic regulators of pluripotency. Cell 128, 747–762 (2007).

    CAS  PubMed  Google Scholar 

  56. Ku, M. et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet. 4, e1000242 (2008).

    PubMed  PubMed Central  Google Scholar 

  57. Zhao, X.D. et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).

    CAS  PubMed  Google Scholar 

  58. Pan, G. et al. Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell 1, 299–312 (2007).

    CAS  PubMed  Google Scholar 

  59. Mikkelsen, T.S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    CAS  PubMed  Google Scholar 

  61. Laurent, L. et al. Dynamic changes in the human methylome during differentiation. Genome Res. 20, 320–331 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mohn, F. et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol. Cell 30, 755–766 (2008).

    CAS  PubMed  Google Scholar 

  65. Meissner, A. et al. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res. 33, 5868–5877 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jackson, M. et al. Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells. Mol. Cell. Biol. 24, 8862–8871 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006).

    CAS  PubMed  Google Scholar 

  68. Chamberlain, S.J., Yee, D. & Magnuson, T. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 26, 1496–1505 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Holm, T.M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005).

    CAS  PubMed  Google Scholar 

  70. Fouse, S. et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2, 160–169 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ng, R.K. et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Boyer, L.A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    CAS  PubMed  Google Scholar 

  73. Chi, A.S. & Bernstein, B.E. Developmental biology. Pluripotent chromatin state. Science 323, 220–221 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Martens, J.H. et al. The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J. 24, 800–812 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bilodeau, S., Kagey, M.H., Frampton, G.M., Rahl, P.B. & Young, R.A. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev. 23, 2484–2489 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lohmann, F. et al. KMT1E mediated H3K9 methylation is required for the maintenance of embryonic stem cells by repressing trophectoderm differentiation. Stem Cells 28, 201–212 (2010).

    CAS  PubMed  Google Scholar 

  78. Rollins, R.A. et al. Large-scale structure of genomic methylation patterns. Genome Res. 16, 157–163 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 39, 457–466 (2007).

    CAS  PubMed  Google Scholar 

  80. Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet. 10, 295–304 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Imamura, M. et al. Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells. BMC Dev. Biol. 6, 34 (2006).

    PubMed  PubMed Central  Google Scholar 

  83. Ramsahoye, B.H. et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc. Natl. Acad. Sci. USA 97, 5237–5242 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Haines, T.R., Rodenhiser, D.I. & Ainsworth, P.J. Allele-specific non-CpG methylation of the Nf1 gene during early mouse development. Dev. Biol. 240, 585–598 (2001).

    CAS  PubMed  Google Scholar 

  85. Dodge, J.E., Ramsahoye, B.H., Wo, Z.G., Okano, M. & Li, E. De novo methylation of MMLV provirus in embryonic stem cells: CpG versus non-CpG methylation. Gene 289, 41–48 (2002).

    CAS  PubMed  Google Scholar 

  86. Cokus, S.J. et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452, 215–219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chan, S.W., Henderson, I.R. & Jacobsen, S.E. Gardening the genome: DNA methylation in Arabidopsis thaliana. Nat. Rev. Genet. 6, 351–360 (2005).

    CAS  PubMed  Google Scholar 

  88. Lomvardas, S. et al. Interchromosomal interactions and olfactory receptor choice. Cell 126, 403–413 (2006).

    CAS  PubMed  Google Scholar 

  89. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Down, T.A. et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat. Biotechnol. 26, 779–785 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wu, S.C. & Zhang, Y. Active DNA demethylation: many roads lead to Rome. Nat. Rev. Mol. Cell Biol. 11, 607–620 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Jeltsch, A. Beyond Watson and Crick: DNA methylation and molecular enzymology of DNA methyltransferases. ChemBioChem 3, 274–293 (2002).

    CAS  PubMed  Google Scholar 

  95. Guenther, M.G., Levine, S.S., Boyer, L.A., Jaenisch, R. & Young, R.A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    CAS  PubMed  Google Scholar 

  97. Boiani, M. & Scholer, H.R. Regulatory networks in embryo-derived pluripotent stem cells. Nat. Rev. Mol. Cell Biol. 6, 872–884 (2005).

    CAS  PubMed  Google Scholar 

  98. Xie, W. et al. Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells. Mol. Cell 33, 417–427 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Daujat, S. et al. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. Nat. Struct. Mol. Biol. 16, 777–781 (2009).

    CAS  PubMed  Google Scholar 

  100. Efroni, S. et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2, 437–447 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gu, H. et al. Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution. Nat. Methods 7, 133–136 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Goren, A. et al. Chromatin profiling by directly sequencing small quantities of immunoprecipitated DNA. Nat. Methods 7, 47–49 (2010).

    CAS  PubMed  Google Scholar 

  103. Xu, J. et al. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 23, 2824–2838 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat. Struct. Mol. Biol. 15, 1176–1183 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Feldman, N. et al. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell Biol. 8, 188–194 (2006).

    CAS  PubMed  Google Scholar 

  106. Cherry, S.R., Biniszkiewicz, D., van Parijs, L., Baltimore, D. & Jaenisch, R. Retroviral expression in embryonic stem cells and hematopoietic stem cells. Mol. Cell. Biol. 20, 7419–7426 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464, 927–931 (2010).

    CAS  PubMed  Google Scholar 

  108. Sen, G.L., Reuter, J.A., Webster, D.E., Zhu, L. & Khavari, P.A. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463, 563–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bröske, A.M. et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat. Genet. 41, 1207–1215 (2009).

    PubMed  Google Scholar 

  110. Trowbridge, J.J., Snow, J.W., Kim, J. & Orkin, S.H. DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5, 442–449 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Tadokoro, Y., Ema, H., Okano, M., Li, E. & Nakauchi, H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J. Exp. Med. 204, 715–722 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Jacobs, J.J., Kieboom, K., Marino, S., DePinho, R.A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    CAS  PubMed  Google Scholar 

  114. Woo, C.J., Kharchenko, P.V., Daheron, L., Park, P.J. & Kingston, R.E. A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 140, 99–110 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Li, G. et al. Jarid2 and PRC2, partners in regulating gene expression. Genes Dev. 24, 368–380 (2010).

    PubMed  PubMed Central  Google Scholar 

  116. Pasini, D. et al. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306–310 (2010).

    CAS  PubMed  Google Scholar 

  117. Peng, J.C. et al. Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139, 1290–1302 (2009).

    PubMed  PubMed Central  Google Scholar 

  118. Shen, X. et al. Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139, 1303–1314 (2009).

    PubMed  PubMed Central  Google Scholar 

  119. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106, 11667–11672 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Guenther, M.G. & Young, R.A. Transcription. Repressive transcription. Science 329, 150–151 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Hochedlinger, K. & Jaenisch, R. Nuclear reprogramming and pluripotency. Nature 441, 1061–1067 (2006).

    CAS  PubMed  Google Scholar 

  123. 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 

  124. Park, I.H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

    CAS  PubMed  Google Scholar 

  125. 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 

  126. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  PubMed  Google Scholar 

  127. Maherali, N. et al. Global epigenetic remodeling in directly reprogrammed fibroblasts. Cell Stem Cell 1, 55–70 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ichida, J.K. et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5, 491–503 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Ng, R.K. & Gurdon, J.B. Epigenetic memory of active gene transcription is inherited through somatic cell nuclear transfer. Proc. Natl. Acad. Sci. USA 102, 1957–1962 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Ng, R.K. & Gurdon, J.B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nat. Cell Biol. 10, 102–109 (2008).

    CAS  PubMed  Google Scholar 

  136. Tamashiro, K.L. et al. Cloned mice have an obese phenotype not transmitted to their offspring. Nat. Med. 8, 262–267 (2002).

    CAS  PubMed  Google Scholar 

  137. Bortvin, A. et al. Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development 130, 1673–1680 (2003).

    CAS  PubMed  Google Scholar 

  138. Blelloch, R. et al. Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus. Stem Cells 24, 2007–2013 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hotchkiss, R.D. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J. Biol. Chem. 175, 315–332 (1948).

    CAS  PubMed  Google Scholar 

  140. Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    CAS  PubMed  Google Scholar 

  141. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    CAS  PubMed  Google Scholar 

  142. Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521–533 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106, 11667–11672 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank C. Bock, Z. Smith and B. Bernstein for comments on the manuscript. A.M. is supported by the Massachusetts Life Science Center, the Pew Charitable Trusts and the US National Institutes of Health Roadmap Initiative on Epigenomics (U01ES017155).

Author information

Authors and Affiliations

  1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA

    Alexander Meissner

  2. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Alexander Meissner

  3. Broad Institute, Cambridge, Massachusetts, USA

    Alexander Meissner

Authors
  1. Alexander Meissner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Meissner.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meissner, A. Epigenetic modifications in pluripotent and differentiated cells. Nat Biotechnol 28, 1079–1088 (2010). https://doi.org/10.1038/nbt.1684

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.1684

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research