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 control of neural precursor cell fate during development

Key Points

  • During embryonic development, pluripotent stem cells undergo sequential fate restriction; that is, the variety of cell types that a stem cell can generate is reduced with each consecutive stage of development.

  • Cells in the neural lineage undergo sequential fate restriction, starting with pluripotent embryonic stem cells, followed by neural stem cells with various temporal- and spatial-specific differentiation capacities, and ending with terminally differentiated neurons and glial cells.

  • The poised state of developmental genes prevents premature cell differentiation while maintaining the capacity of the genes to be activated in the future.

  • Cells at each stage of development have distinct sets of poised genes corresponding to their differentiation potential.

  • The poised state is maintained by reversible short-term silencing that is different from the permanent long-term silencing often found in differentiated cells.

  • Different types and combinations of epigenetic marks, including the modification of histones or DNA, establish long-term and short-term repression, although the precise mechanisms distinguishing these modes of repression remain unclear.

Abstract

The temporally and spatially restricted nature of the differentiation capacity of cells in the neural lineage has been studied extensively in recent years. Epigenetic control of developmental genes, which is heritable through cell divisions, has emerged as a key mechanism defining the differentiation potential of cells. Short-term or reversible repression of developmental genes puts them in a 'poised state', ready to be activated in response to differentiation-inducing cues, whereas long-term or permanent repression of developmental genes restricts the cell fates they regulate. Here, we review the molecular mechanisms that underlie the establishment and regulation of differentiation potential along the neural lineage during development.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Differentiation potential of stem cells in each developmental stage.
Figure 2: Summary of the transcriptional state (active, poised or repressed) of various classes of developmental genes.
Figure 3: Stage-dependent regulation of neural precursor cell fate.

Similar content being viewed by others

References

  1. Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Hirabayashi, Y. & Gotoh, Y. Stage-dependent fate determination of neural precursor cells in mouse forebrain. Neurosci. Res. 51, 331–336 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Molyneaux, B. J., Arlotta, P., Menezes, J. R. & Macklis, J. D. Neuronal subtype specification in the cerebral cortex. Nature Rev. Neurosci. 8, 427–437 (2007).

    Article  CAS  Google Scholar 

  4. Frantz, G. D. & McConnell, S. K. Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 17, 55–61 (1996). This study showed that, late in development, neocortical NPCs lose the capacity to generate neurons that are normally generated at an earlier stage, possibly owing to a cell-intrinsic mechanism.

    Article  CAS  PubMed  Google Scholar 

  5. Desai, A. R. & McConnell, S. K. Progressive restriction in fate potential by neural progenitors during cerebral cortical development. Development 127, 2863–2872 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Yoo, A. S. & Crabtree, G. R. ATP-dependent chromatin remodeling in neural development. Curr. Opin. Neurobiol. 19, 120–126 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Borrelli, E., Nestler, E. J., Allis, C. D. & Sassone-Corsi, P. Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mehler, M. F. Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog. Neurobiol. 86, 305–341 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Copray, S., Huynh, J. L., Sher, F., Casaccia-Bonnefil, P. & Boddeke, E. Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging. Glia 57, 1579–1587 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006). References 11 and 12 identified a large set of PcG target genes, which are enriched for genes that control development and transcription in ESCs. See also reference 105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Endoh, M. et al. Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development 135, 1513–1524 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006). References 15 and 16 showed that key genes for development are poised for activation in ESCs by the combination of histone modifications H3K27me3 and H3K4me3.

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007). This study used ChIP–seq technology to describe the genome-wide histone modification state of mouse ESCs, NPCs and embryonic fibroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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). An important study tracking genome-wide epigenetic modification by PcG proteins and DNA methylation during differentiation of ESCs to neural progenitors and to terminally differentiated neurons.

    Article  CAS  PubMed  Google Scholar 

  20. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008). This study provided the first genome-wide DNA methylation profile at nucleotide resolution in ESCs, ESC-derived NPCs and other primary tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fouse, S. D. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chong, J. A. et al. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949–957 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Schoenherr, C. J. & Anderson, D. J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Lunyak, V. V. et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Ballas, N. & Mandel, G. The many faces of REST oversee epigenetic programming of neuronal genes. Curr. Opin. Neurobiol. 15, 500–506 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005). This study showed the roles of REST in long-term repression in terminally differentiated fibroblasts and in short-term repression in ESCs or neural progenitors.

    Article  CAS  PubMed  Google Scholar 

  28. Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H. & Majumder, S. REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453, 223–227 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jorgensen, H. F. et al. REST selectively represses a subset of RE1-containing neuronal genes in mouse embryonic stem cells. Development 136, 715–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Loh, Y. H. et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genet. 38, 431–440 (2006).

    CAS  PubMed  Google Scholar 

  32. Jørgensen, H. F., Chen, Z. F., Merkenschlager, M. & Fisher, A. G. Is REST required for ESC pluripotency? Nature 457, E4–E5; discussion E7 (2009).

    Article  CAS  Google Scholar 

  33. Buckley, N. J., Johnson, R., Sun, Y. M. & Stanton, L. W. Is REST a regulator of pluripotency? Nature 457, E5–E6; discussion E7 (2009).

    Article  CAS  Google Scholar 

  34. Johnson, R. et al. REST regulates distinct transcriptional networks in embryonic and neural stem cells. PLoS Biol. 6, e256 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Shi, Y. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Roopra, A., Qazi, R., Schoenike, B., Daley, T. J. & Morrison, J. F. Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes. Mol. Cell 14, 727–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Tahiliani, M. et al. The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 447, 601–605 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Iwase, S. et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077–1088 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Schoeftner, S. & Blasco, M. A. A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs. EMBO J. 28, 2323–2336 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Burgold, T. et al. The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PLoS ONE 3, e3034 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lee, E. R., Murdoch, F. E. & Fritsch, M. K. High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid. Stem Cells 25, 2191–2199 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Hirabayashi, Y. et al. Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63, 600–613 (2009). This paper shows that PcG proteins restrict the neurogenic potential of NPCs in the late stage of neocortical development and cause the developmental-stage-dependent fate switch.

    Article  CAS  PubMed  Google Scholar 

  44. Golebiewska, A., Atkinson, S. P., Lako, M. & Armstrong, L. Epigenetic landscaping during hESC differentiation to neural cells. Stem Cells 27, 1298–1308 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Wen, B., Wu, H., Shinkai, Y., Irizarry, R. A. & Feinberg, A. P. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nature Genetics 41, 246–250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Westbrook, T. F. et al. SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452, 370–374 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ringrose, L. & Paro, R. Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 134, 223–232 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Schuettengruber, B. & Cavalli, G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development 136, 3531–3542 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Sing, A. et al. A vertebrate Polycomb response element governs segmentation of the posterior hindbrain. Cell 138, 885–897 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lan, F., Nottke, A. C. & Shi, Y. Mechanisms involved in the regulation of histone lysine demethylases. Curr. Opin. Cell Biol. 20, 316–325 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma, D. K., Guo, J. U., Ming, G. L. & Song, H. DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation. Cell Cycle 8, 1526–1531 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Walsh, C. & Cepko, C. L. Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science 255, 434–440 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Noctor, S. C., Martinez-Cerdeno, V. & Kriegstein, A. R. Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. J. Comp. Neurol. 508, 28–44 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Costa, M. R., Bucholz, O., Schroeder, T. & Gotz, M. Late origin of glia-restricted progenitors in the developing mouse cerebral cortex. Cereb. Cortex 19, i135–i143 (2009).

    Article  PubMed  Google Scholar 

  56. Qian, X. et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Shen, Q. et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nature Neurosci. 9, 743–751 (2006). References 56 and 57 show that isolated mouse cortical stem cells grown in clonal cultures recapitulated the sequential generation of early-born neurons, late-born neurons and glia that is observed in vivo .

    Article  CAS  PubMed  Google Scholar 

  58. Mizutani, K. & Saito, T. Progenitors resume generating neurons after temporary inhibition of neurogenesis by Notch activation in the mammalian cerebral cortex. Development 132, 1295–1304 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. McConnell, S. K. & Kaznowski, C. E. Cell cycle dependence of laminar determination in developing neocortex. Science 254, 282–285 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Rajan, P. & McKay, R. D. Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 18, 3620–3629 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Johe, K. K., Hazel, T. G., Muller, T., Dugich-Djordjevic, M. M. & McKay, R. D. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 10, 3129–3140 (1996). The authors established an in vitro system to culture NPCs and identified extracellular factors that direct lineage commitment, enabling analysis of the differentiation capacity of a given NPC.

    Article  CAS  PubMed  Google Scholar 

  62. He, F. et al. A positive autoregulatory loop of Jak–STAT signaling controls the onset of astrogliogenesis. Nature Neurosci. 8, 616–625 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the JAK–STAT signaling pathway. Science 278, 477–483 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Barnabe-Heider, F. et al. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48, 253–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Yoshimatsu, T. et al. Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex. Development 133, 2553–2563 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Derouet, D. et al. Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor. Proc. Natl Acad. Sci. USA 101, 4827–4832 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Uemura, A. et al. Cardiotrophin-like cytokine induces astrocyte differentiation of fetal neuroepithelial cells via activation of STAT3. Cytokine 18, 1–7 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Song, M. R. & Ghosh, A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nature Neurosci. 7, 229–235 (2004).

    Article  PubMed  CAS  Google Scholar 

  69. Takizawa, T. et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev. Cell 1, 749–758 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Molne, M. et al. Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J. Neurosci. Res. 59, 301–311 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Fan, G. et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK–STAT signaling. Development 132, 3345–3356 (2005). References 69 and 71 showed that DNA methylation at gene regulatory elements of GFAP and JAK–STAT pathway components block astrocytic differentiation in early neocortical development.

    Article  CAS  PubMed  Google Scholar 

  72. Namihira, M., Nakashima, K. & Taga, T. Developmental stage dependent regulation of DNA methylation and chromatin modification in a immature astrocyte specific gene promoter. FEBS Lett. 572, 184–188 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Teter, B., Finch, C. E. & Condorelli, D. F. DNA methylation in the glial fibrillary acidic protein gene: map of CpG methylation sites and summary of analysis by restriction enzymes and by LMPCR. J. Neurosci. Res. 39, 708–709 (1994).

    Article  CAS  PubMed  Google Scholar 

  74. Namihira, M. et al. Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev. Cell 16, 245–255 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Naka, H., Nakamura, S., Shimazaki, T. & Okano, H. Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nature Neurosci. 11, 1014–1023 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Setoguchi, H. et al. Methyl-CpG binding proteins are involved in restricting differentiation plasticity in neurons. J. Neurosci. Res. 84, 969–979 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Kohyama, J. et al. Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Proc. Natl Acad. Sci. USA 105, 18012–18017 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hirabayashi, Y. et al. The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 131, 2791–2801 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Muroyama, Y., Kondoh, H. & Takada, S. Wnt proteins promote neuronal differentiation in neural stem cell culture. Biochem. Biophys. Res. Commun. 313, 915–921 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Israsena, N., Hu, M., Fu, W., Kan, L. & Kessler, J. A. The presence of FGF2 signaling determines whether β-catenin exerts effects on proliferation or neuronal differentiation of neural stem cells. Dev. Biol. 268, 220–231 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Zhou, C. J., Borello, U., Rubenstein, J. L. & Pleasure, S. J. Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway. Neuroscience 142, 1119–1131 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Lyu, J., Yamamoto, V. & Lu, W. Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Dev. Cell 15, 773–780 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Ivaniutsin, U., Chen, Y., Mason, J. O., Price, D. J. & Pratt, T. Adenomatous polyposis coli is required for early events in the normal growth and differentiation of the developing cerebral cortex. Neural Dev. 4, 3 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Guillemot, F. Cell fate specification in the mammalian telencephalon. Prog. Neurobiol. 83, 37–52 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Guillemot, F. Cellular and molecular control of neurogenesis in the mammalian telencephalon. Curr. Opin. Cell Biol. 17, 639–647 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Sun, Y. et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Roman-Trufero, M. et al. Maintenance of undifferentiated state and self-renewal of embryonic neural stem cells by Polycomb protein Ring1B. Stem Cells 27, 1559–1570 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fasano, C. A. et al. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1, 87–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. He, S. et al. Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev. Biol. 328, 257–272 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fasano, C. A. et al. Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev. 23, 561–574 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lessard, J. et al. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pietersen, A. M. et al. EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res. 10, R109 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Kessaris, N. et al. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nature Neurosci. 9, 173–179 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Petryniak, M. A., Potter, G. B., Rowitch, D. H. & Rubenstein, J. L. Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain. Neuron 55, 417–433 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lim, D. A. et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458, 529–533 (2009). This work showed that the TrxG member MLL is required for resolution of the bivalent state of the Dlx2 locus and for neurogenesis in the postnatal brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sher, F. et al. Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells 26, 2875–2883 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Barres, B. A., Lazar, M. A. & Raff, M. C. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120, 1097–1108 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Mabie, P. C. et al. Bone morphogenetic proteins induce astroglial differentiation of oligodendroglial-astroglial progenitor cells. J. Neurosci. 17, 4112–4120 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kondo, T. & Raff, M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754–1757 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Kondo, T. & Raff, M. Chromatin remodeling and histone modification in the conversion of oligodendrocyte precursors to neural stem cells. Genes Dev. 18, 2963–2972 (2004). References 100 and 101 showed that chromatin remodelling is involved in the reprogramming of lineage-committed oligodendrocytes into multipotent NPCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lyssiotis, C. A. et al. Inhibition of histone deacetylase activity induces developmental plasticity in oligodendrocyte precursor cells. Proc. Natl Acad. Sci. USA 104, 14982–14987 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liu, A. et al. The glial or neuronal fate choice of oligodendrocyte progenitors is modulated by their ability to acquire an epigenetic memory. J. Neurosci. 27, 7339–7343 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schwartz, Y. B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nature Rev. Genet. 8, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  108. Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008). This study describes gene expression profiling and chromatin-state maps of fully and partially reprogrammed cell lines; treatment with DNMT inhibitors was found to improve the efficiency of reprogramming.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).

    CAS  PubMed  Google Scholar 

  110. Hochedlinger, K. & Plath, K. Epigenetic reprogramming and induced pluripotency. Development 136, 509–523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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  PubMed  Google Scholar 

  112. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Stadtfeld, M., Brennand, K. & Hochedlinger, K. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr. Biol. 18, 890–894 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kim, J. B. et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646–650 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Kim, J. B. et al. Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411–419 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649–653 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Hester, M. E. et al. Two factor reprogramming of human neural stem cells into pluripotency. PLoS ONE 4, e7044 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shi, Y. et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2, 525–528 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  121. Trojer, P. & Reinberg, D. Facultative heterochromatin: is there a distinctive molecular signature? Mol. Cell 28, 1–13 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  124. Rai, K. et al. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and Gadd45. Cell 135, 1201–1212 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nature Rev. Mol. Cell Biol. 6, 838–849 (2005).

    Article  CAS  Google Scholar 

  126. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rice, J. C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591–1598 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Loyola, A. et al. The HP1α–CAF1–SetDB1-containing complex provides H3K9me1 for Suv39-mediated K9me3 in pericentric heterochromatin. EMBO Rep. 10, 769–775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  130. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Klose, R. J. & Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nature Rev. Mol. Cell Biol. 8, 307–318 (2007).

    Article  CAS  Google Scholar 

  132. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Nottke, A., Colaiacovo, M. P. & Shi, Y. Developmental roles of the histone lysine demethylases. Development 136, 879–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wissmann, M. et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nature Cell Biol. 9, 347–353 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Cao, R. & Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14, 155–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. 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, 491–502 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kalantry, S. et al. The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation. Nature Cell Biol. 8, 195–202 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. 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  PubMed  Google Scholar 

  140. Mager, J., Montgomery, N. D., de Villena, F. P. & Magnuson, T. Genome imprinting regulated by the mouse Polycomb group protein Eed. Nature Genet. 33, 502–507 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. van Driel, R., Fransz, P. F. & Verschure, P. J. The eukaryotic genome: a system regulated at different hierarchical levels. J. Cell Sci. 116, 4067–4075 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Misteli, T. Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Williams, R. R. et al. Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J. Cell Sci. 119, 132–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Kosak, S. T. & Groudine, M. Form follows function: the genomic organization of cellular differentiation. Genes Dev. 18, 1371–1384 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Perry, P. et al. A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction. Cell Cycle 3, 1645–1650 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Hiratani, I., Takebayashi, S., Lu, J. & Gilbert, D. M. Replication timing and transcriptional control: beyond cause and effect — part II. Curr. Opin. Genet. Dev. 19, 142–149 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hiratani, I. et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gaspar-Maia, A. et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 460, 863–868 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lee, S. & Lee, S. K. Crucial roles of histone-modifying enzymes in mediating neural cell-type specification. Curr. Opin. Neurobiol. 20, 29–36 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Shahbazian, M. D. & Grunstein, M. Functions of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem. 76, 75–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Hsieh, J., Nakashima, K., Kuwabara, T., Mejia, E. & Gage, F. H. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc. Natl Acad. Sci. USA 101, 16659–16664 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yu, I. T. et al. Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation. Neuropharmacology 56, 473–480 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Montgomery, R. L., Hsieh, J., Barbosa, A. C., Richardson, J. A. & Olson, E. N. Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development. Proc. Natl Acad. Sci. USA 106, 7876–7881 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shaked, M. et al. Histone deacetylases control neurogenesis in embryonic brain by inhibition of BMP2/4 signaling. PLoS ONE 3, e2668 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Koyano-Nakagawa, N., Wettstein, D. & Kintner, C. Activation of Xenopus genes required for lateral inhibition and neuronal differentiation during primary neurogenesis. Mol. Cell. Neurosci. 14, 327–339 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Lee, S., Lee, B., Lee, J. W. & Lee, S. K. Retinoid signaling and Neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62, 641–654 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3–Smad1 complex bridged by p300. Science 284, 479–482 (1999).

    Article  CAS  PubMed  Google Scholar 

  160. Jepsen, K. et al. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450, 415–419 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Hermanson, O., Jepsen, K. & Rosenfeld, M. G. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934–939 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Seo, S., Richardson, G. A. & Kroll, K. L. The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD. Development 132, 105–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Lessard, J. et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Waddington, C. H. The Strategy of the Genes. (Allen and Unwin, London, 1957).

    Google Scholar 

  166. Tzouanacou, E., Wegener, A., Wymeersch, F. J., Wilson, V. & Nicolas, J. F. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev. Cell 17, 365–376 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Yuan, P. et al. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev. 23, 2507–2520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bilodeau, S. et al. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev. 23, 2484–2489 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank H. Y. Chang, H. Koseki and T.A. Endo and the reviewers for helpful suggestions. We apologize to all researchers whose work could not be cited owing to space limitation. The authors' work is supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, from the Core Research for Evolutional Science and Technology (CREST) programme of the Japan Science and Technology Agency and from the Global COE Program (Integrative Life Science Based on the Study of Biosignalling Mechanisms), MEXT, Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yukiko Gotoh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Yukiko Gotoh's homepage

Glossary

Developmental genes

Genes that encode key regulators of developmental processes.

Nucleosome

The basic building unit of chromatin comprising 147 bp of DNA wrapped around a histone octamer of two molecules of each of the four histones H2A, H2B, H3 and H4.

Neural genes

Genes expressed during the step of fate commitment from pluripotent cells to neural cells.

Neuronal genes

Genes expressed in cells committed to the neuronal lineage that are important for terminal differentiation and function of neuronal cells.

Transposons

Mobile genetic elements that use replication machineries of host cells to proliferate. To prevent genomic instability caused by insertion of transposons, host cells have evolved mechanisms to silence the mobility of these elements.

Telomeres

A tandem DNA sequence that caps the ends of linear chromosomes and protects them from degradation and chromosome end fusion.

Imprinted genes

Genes expressed from only one allele in a manner that depends on the parent of origin.

Pericentric heterochromatin

A typical constitutive heterochromatin region that is juxtaposed to the centromere and remains condensed throughout the cell cycle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirabayashi, Y., Gotoh, Y. Epigenetic control of neural precursor cell fate during development. Nat Rev Neurosci 11, 377–388 (2010). https://doi.org/10.1038/nrn2810

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2810

This article is cited by

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