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.

Stability and flexibility of epigenetic gene regulation in mammalian development

Abstract

During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences — transposons, imprinted genes and pluripotency-associated genes — in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Epigenetic gene regulation during mammalian development.
Figure 2: Epigenetic regulation of pluripotency-associated genes and developmental genes during the differentiation of somatic cells and germ cells.
Figure 3: Developmental regulation of imprinting and X-chromosome inactivation.
Figure 4: Reprogramming of epigenetic marks in the germ line and the early embryo.

References

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

    Article  CAS  Google Scholar 

  2. Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14, R47–R58 (2005).

    Article  CAS  Google Scholar 

  3. Allis, C. D., Jenuwein, T. & Reinberg, D. (eds) Epigenetics (Cold Spring Harbor Laboratory Press, Woodbury, 2007).

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Turner, B. M. Defining an epigenetic code. Nature Cell Biol. 9, 2–6 (2007).

    Article  CAS  Google Scholar 

  7. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  9. Szutorisz, H. et al. Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage. Mol. Cell. Biol. 25, 1804–1820 (2005).

    Article  CAS  Google Scholar 

  10. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006).

    Article  CAS  Google Scholar 

  13. Ohm, J. E. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genet. 39, 237–242 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nature Rev. Cancer 5, 615–625 (2005).

    Article  CAS  Google Scholar 

  16. Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).

    Article  CAS  Google Scholar 

  17. Boiani, M., Eckardt, S., Scholer, H. R. & McLaughlin, K. J. Oct4 distribution and level in mouse clones: consequences for pluripotency. Genes Dev. 16, 1209–1219 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Ancelin, K. et al. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nature Cell Biol. 8, 623–630 (2006).

    Article  CAS  Google Scholar 

  20. Maatouk, D. M. et al. DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 133, 3411–3418 (2006).

    Article  CAS  Google Scholar 

  21. Surani, A. & Reik, W. in Epigenetics (eds Allis, C. D., Jenuwein, T. & Reinberg, D.) 315–327 (Cold Spring Harbor Laboratory Press, Woodbury, 2007).

    Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  23. Barlow, D. P. Methylation and imprinting: from host defense to gene regulation? Science 260, 309–310 (1993).

    Article  ADS  CAS  Google Scholar 

  24. 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).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  26. Jelinic, P., Stehle, J. C. & Shaw, P. The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation. PLoS Biol. [online] 4, e355 (2006) (doi:10.1371/journal.pbio.0040355).

    Article  Google Scholar 

  27. Howell, C. Y. et al. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104, 829–838 (2001).

    Article  CAS  Google Scholar 

  28. Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).

    Article  ADS  CAS  Google Scholar 

  29. Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810–813 (2002)

    Article  ADS  CAS  Google Scholar 

  30. Mancini-Dinardo, D., Steele, S. J., Levorse, J. M., Ingram, R. S. & Tilghman, S. M. Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes. Genes Dev. 20, 1268–1282 (2006).

    Article  CAS  Google Scholar 

  31. Lewis, A. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nature Genet. 36, 1291–1295 (2004).

    Article  CAS  Google Scholar 

  32. Umlauf, D. et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nature Genet. 36, 1296–1300 (2004).

    Article  CAS  Google Scholar 

  33. Kanduri, C., Thakur, N. & Pandey, R. R. The length of the transcript encoded from the Kcnq1ot1 antisense promoter determines the degree of silencing. EMBO J. 25, 2096–2106 (2006).

    Article  CAS  Google Scholar 

  34. Lewis, A. et al. Epigenetic dynamics of the Kcnq1 imprinted domain in the early embryo. Development 133, 4203–4210 (2006).

    Article  CAS  Google Scholar 

  35. Chaumeil, J., Le Baccon, P., Wutz, A. & Heard, E. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev. 20, 2223–2227 (2006).

    Article  CAS  Google Scholar 

  36. Verona, R. I., Mann, M. R. & Bartolomei, M. S. Genomic imprinting: intricacies of epigenetic regulation in clusters. Annu. Rev. Cell Dev. Biol. 19, 237–259 (2003).

    Article  CAS  Google Scholar 

  37. Kurukuti, S. et al. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc. Natl Acad. Sci. USA 103, 10684–10689 (2006).

    Article  ADS  CAS  Google Scholar 

  38. Okamoto, I. et al. Evidence for de novo imprinted X-chromosome inactivation independent of meiotic inactivation in mice. Nature 438, 369–373 (2005).

    Article  ADS  CAS  Google Scholar 

  39. Sado, T. et al. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev. Biol. 225, 294–303 (2000).

    Article  CAS  Google Scholar 

  40. Kohlmaier, A. et al. A chromosomal memory triggered by Xist regulates histone methylation in X inactivation. PLoS Biol. [online] 2, e171 (2004) (doi:10.1371/journal.pbio.0020171).

    Article  Google Scholar 

  41. Mak, W. et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 303, 666–669 (2004).

    Article  ADS  CAS  Google Scholar 

  42. Okamoto, I., Otte, A. P., Allis, C. D., Reinberg, D. & Heard, E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303, 644–649 (2004).

    Article  ADS  CAS  Google Scholar 

  43. Heard, E. & Disteche, C. M. Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev. 20, 1848–1867 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Hajkova, P. et al. Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15–23 (2002).

    Article  CAS  Google Scholar 

  46. Lee, J. et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129, 1807–1817 (2002).

    Article  CAS  Google Scholar 

  47. Seki, Y. et al. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev. Biol. 278, 440–458 (2005).

    Article  CAS  Google Scholar 

  48. 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).

    Article  CAS  Google Scholar 

  49. 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. [online] 6, 34 (2006) (doi:10.1186/1471-213X-6-34).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  52. Dean, W. et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc. Natl Acad. Sci. USA 98, 13734–13738 (2001).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  54. Nakamura, T. et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature Cell Biol. 9, 64–71 (2007).

    Article  CAS  Google Scholar 

  55. Morgan, H. D., Dean, W., Coker, H. A., Reik, W. & Petersen-Mahrt, S. K. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J. Biol. Chem. 279, 52353–52360 (2004).

    Article  CAS  Google Scholar 

  56. Gehring, M. et al. DEMETER DNA glycosylase establishes MEDEA Polycomb gene self-imprinting by allele-specific demethylation. Cell 124, 495–506 (2006).

    Article  CAS  Google Scholar 

  57. Morales-Ruiz, T. et al. DEMETER and REPRESSOR OF SILENCING 1 encode 5-methylcytosine DNA glycosylases. Proc. Natl Acad. Sci. USA 103, 6853–6858 (2006).

    Article  ADS  CAS  Google Scholar 

  58. Barreto, G. et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445, 671–675 (2007).

    Article  CAS  Google Scholar 

  59. Reik, W. & Walter, J. Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote. Nature Genet. 27, 255–256 (2001).

    Article  CAS  Google Scholar 

  60. Smith, A. G. Embryo-derived stem cells: of mice and men. Annu. Rev. Cell Dev. Biol. 17, 435–462 (2002).

    Article  Google Scholar 

  61. Whitelaw, N. C. & Whitelaw, E. How lifetimes shape epigenotype within and across generations. Hum. Mol. Genet. 15, R131–R137 (2006).

    Article  CAS  Google Scholar 

  62. Blewitt, M. E., Vickaryous, N. K., Paldi, A., Koseki, H. & Whitelaw, E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. [online] 2, e49 (2006) (doi:10.1371/journal.pgen.0020049).

    Article  CAS  Google Scholar 

  63. Bean, C. J., Schaner, C. E. & Kelly, W. G. Meiotic pairing and imprinted X chromatin assembly in Caenorhabditis elegans. Nature Genet. 36, 100–105 (2004).

    Article  CAS  Google Scholar 

  64. Namekawa, S. H. et al. Postmeiotic sex chromatin in the male germline of mice. Curr. Biol. 16, 660–667 (2006).

    Article  CAS  Google Scholar 

  65. Rossant, J. Lineage development and polar asymmetries in the peri-implantation mouse blastocyst. Semin. Cell Dev. Biol. 15, 573–581 (2004).

    Article  Google Scholar 

  66. Torres-Padilla, M.E., Parfitt, D.E., Kouzarides, T. & Zernicka-Goetz, M. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214–218 (2007).

    Article  ADS  CAS  Google Scholar 

  67. Yang, X. et al. Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nature Genet. 39, 295–302 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank all my colleagues, past and present, for their contributions to the work and ideas described in this paper, especially W. Dean, F. Santos, A. Lewis, and G. Smits. Funding from the Biotechnology and Biological Sciences Research Council, the Medical Research Council, the European Union Epigenome Network of Excellence, CellCentric and the Department of Trade & Industry is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author is a consultant to CellCentric (Cambridge, UK), a small company that takes epigenetic approaches to medicine.

Additional information

Reprints and permissions information is available at http://npg.nature.com/reprintsandpermissions.

Correspondence should be addressed to the author (wolf.reik@bbsrc.ac.uk).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007). https://doi.org/10.1038/nature05918

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05918

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing