Epigenetic Control of Neural Stem Cell Self-Renewal and Specification

Part of the Advances in Biomedical Research book series (ABIR, volume 1)


Neural stem cells have the ability to self-renew and to differentiate. Epigenetic control has been shown to play an important role in regulating both. Recent progress in epigenetics provides novel perspective on regulation of neural stem cell maintenance and fate-specification, which, in turn, offers new strategies to combat neurodegenerative diseases using stem cell-based therapies. In this chapter, we attempt to cover recent advances in this exciting area with three aspects of epigenetic control: histone modification, DNA methylation and micro-RNAs. Understanding regulatory mechanisms of neural stem cell self-renewal and specification will offer new tools for clinical application of neural stem cells in the treatment of neurodegenerative diseases and brain injury.


Neural stem cells epigenetics histone modification DNA methylation microRNAs nuclear receptor TLX (NR2E1) 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gage FH. (2000) Mammalian neural stem cells. Science; 287:1433–1438.PubMedCrossRefGoogle Scholar
  2. 2.
    Bernstein BE, Meissner A, Lander ES. (2007) The mammalian epigenome. Cell; 128:669–681.PubMedCrossRefGoogle Scholar
  3. 3.
    Hsieh J, Gage FH. (2004) Epigenetic control of neural stem cell fate. Current opinion in genetics & development; 14:461–469.CrossRefGoogle Scholar
  4. 4.
    Shi Y, Sun G, Zhao C, Stewart R. (2008) Neural stem cell self-renewal. Critical reviews in oncology/hematology; 65:43–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Jenuwein T, Allis CD. (2001) Translating the histone code. Science; 293:1074–1080.PubMedCrossRefGoogle Scholar
  6. 6.
    Thiagalingam S, Cheng KH, Lee HJ, et al. (2003) Histone deacetylases: unique players in shaping the epigenetic histone code. Annals of the New York Academy of Sciences; 983:84–100.PubMedCrossRefGoogle Scholar
  7. 7.
    Sun G, Yu RT, Evans RM, Shi Y. (2007) Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proceedings of the National Academy of Sciences of the United States of America; 104:15282–15287.PubMedCrossRefGoogle Scholar
  8. 8.
    Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proceedings of the National Academy of Sciences of the United States of America; 101:16659–16664.PubMedCrossRefGoogle Scholar
  9. 9.
    Shi Y, Chichung Lie D, Taupin P, et al. (2004) Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature; 427:78–83.PubMedCrossRefGoogle Scholar
  10. 10.
    Li W, Sun G, Yang S, et al. (2008) Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain. Molecular endocrinology; 22:56–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Groszer M, Erickson R, Scripture-Adams DD, et al. (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science; 294:2186–2189.PubMedCrossRefGoogle Scholar
  12. 12.
    Qiu J, Takagi Y, Harada J, et al. (2004) Regenerative response in ischemic brain restricted by p21cip1/waf1. The Journal of experimental medicine; 199:937–945.PubMedCrossRefGoogle Scholar
  13. 13.
    Kippin TE, Martens DJ, van der Kooy D. (2005) p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes & development; 19:756–767.CrossRefGoogle Scholar
  14. 14.
    Siebzehnrubl FA, Buslei R, Eyupoglu IY, et al. (2007) Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells. Experimental brain research. Experimentelle Hirnforschung. Experimentation cerebrale; 176:672–678.PubMedGoogle Scholar
  15. 15.
    Shen S, Li J, Casaccia-Bonnefil P. (2005) Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. The Journal of cell biology; 169:577–589.PubMedCrossRefGoogle Scholar
  16. 16.
    Lyssiotis CA, Walker J, Wu C, et al. (2007) Inhibition of histone deacetylase activity induces developmental plasticity in oligodendrocyte precursor cells. Proceedings of the National Academy of Sciences of the United States of America; 104:14982–14987.PubMedCrossRefGoogle Scholar
  17. 17.
    Zencak D, Lingbeek M, Kostic C, et al. (2005) Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. The Journal of neuroscience; 25:5774–5783.PubMedCrossRefGoogle Scholar
  18. 18.
    Molofsky AV, Pardal R, Iwashita T, et al. (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature; 425:962–967.PubMedCrossRefGoogle Scholar
  19. 19.
    Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R. (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes & development; 19:1432–1437.CrossRefGoogle Scholar
  20. 20.
    Takizawa T, Nakashima K, Namihira M, et al. (2001) DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Developmental cell; 1:749–758.PubMedCrossRefGoogle Scholar
  21. 21.
    Jepsen K, Solum D, Zhou T, et al. (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature; 450:415–419.PubMedCrossRefGoogle Scholar
  22. 22.
    Hermanson O, Jepsen K, Rosenfeld MG. (2002) N-CoR controls differentiation of neural stem cells into astrocytes. Nature; 419:934–939.PubMedCrossRefGoogle Scholar
  23. 23.
    Privalsky ML. (2004) The role of corepressors in transcriptional regulation by nuclear hormone receptors. Annual review of physiology; 66:315–360.PubMedCrossRefGoogle Scholar
  24. 24.
    Hong SH, Privalsky ML. (1999) Retinoid isomers differ in the ability to induce release of SMRT corepressor from retinoic acid receptor-alpha. The Journal of biological chemistry; 274:2885–2892.PubMedCrossRefGoogle Scholar
  25. 25.
    Mark M, Ghyselinck NB, Chambon P. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annual review of pharmacology and toxicology; 46:451–480.PubMedCrossRefGoogle Scholar
  26. 26.
    Maden M. (2002) Retinoid signalling in the development of the central nervous system. Nature reviews; 3:843–853.PubMedCrossRefGoogle Scholar
  27. 27.
    Feng J, Fouse S, Fan G. (2007) Epigenetic regulation of neural gene expression and neuronal function. Pediatric research; 61:58R–63R.PubMedCrossRefGoogle Scholar
  28. 28.
    Sharma RP, Grayson DR, Guidotti A, Costa E. (2005) Chromatin, DNA methylation and neuron gene regulation – the purpose of the package. Journal of psychiatry & neuroscience; 30:257–263.Google Scholar
  29. 29.
    Li E. (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nature reviews. Genetics; 3:662–673.PubMedGoogle Scholar
  30. 30.
    Wu H, Sun YE. (2006) Epigenetic regulation of stem cell differentiation. Pediatric research; 59:21R–25R.PubMedCrossRefGoogle Scholar
  31. 31.
    Okano M, Bell DW, Haber DA, Li E. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell; 99:247–257.PubMedCrossRefGoogle Scholar
  32. 32.
    Fan G, Martinowich K, Chin MH, et al. (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development; 132:3345–3356.PubMedCrossRefGoogle Scholar
  33. 33.
    Fan G, Beard C, Chen RZ, et al. (2001) DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. Journal of neuroscience research; 21:788–797.Google Scholar
  34. 34.
    Feng J, Chang H, Li E, Fan G. (2005) Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. Journal of neuroscience research; 79:734–746.PubMedCrossRefGoogle Scholar
  35. 35.
    Watanabe D, Suetake I, Tajima S, Hanaoka K. (2004) Expression of Dnmt3b in mouse hematopoietic progenitor cells and spermatogonia at specific stages. Gene expression patterns; 5:43–49.PubMedCrossRefGoogle Scholar
  36. 36.
    Bai S, Ghoshal K, Datta J, et al. (2005) DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2. Molecular and cellular biology; 25:751–766.PubMedCrossRefGoogle Scholar
  37. 37.
    Shimozaki K, Namihira M, Nakashima K, Taga T. (2005) Stage- and site-specific DNA demethylation during neural cell development from embryonic stem cells. Journal of neurochemistry; 93:432–439.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen WG, Chang Q, Lin Y, et al. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science; 302:885–889.PubMedCrossRefGoogle Scholar
  39. 39.
    Martinowich K, Hattori D, Wu H, et al. (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science; 302:890–893.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhao X, Ueba T, Christie BR, et al. (2003) Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proceedings of the National Academy of Sciences of the United States of America; 100:6777–6782.PubMedCrossRefGoogle Scholar
  41. 41.
    Ballas N, Mandel G. (2005) The many faces of REST oversee epigenetic programming of neuronal genes. Current opinion in neurobiology; 15:500–506.PubMedCrossRefGoogle Scholar
  42. 42.
    Jepsen K, Hermanson O, Onami TM, et al. (2000) Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell; 102:753–763.PubMedCrossRefGoogle Scholar
  43. 43.
    Naruse Y, Aoki T, Kojima T, Mori N. (1999) Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proceedings of the National Academy of Sciences of the United States of America; 96:13691–13696.PubMedCrossRefGoogle Scholar
  44. 44.
    Ooi L, Wood IC. (2007) Chromatin crosstalk in development and disease: lessons from REST. Nature review. Genetics; 8:544–554.PubMedGoogle Scholar
  45. 45.
    Greenway DJ, Street M, Jeffries A, Buckley NJ. (2007) RE1 Silencing transcription factor maintains a repressive chromatin environment in embryonic hippocampal neural stem cells. Stem cells; 25:354–363.PubMedCrossRefGoogle Scholar
  46. 46.
    Kuwabara T, Hsieh J, Nakashima K, Taira K, Gage FH. (2004) A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell; 116:779–793.PubMedCrossRefGoogle Scholar
  47. 47.
    Otto SJ, McCorkle SR, Hover J, et al. (2007) A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions. Journal of neuroscience research; 27:6729–6739.Google Scholar
  48. 48.
    Wu JI, Lessard J, Olave IA, et al. (2007) Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron; 56:94–108.PubMedCrossRefGoogle Scholar
  49. 49.
    Sahin M, Greer PL, Lin MZ, et al. (2005) Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron; 46:191–204.PubMedCrossRefGoogle Scholar
  50. 50.
    Shamah SM, Lin MZ, Goldberg JL, et al. (2001) EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell; 105:233–244.PubMedCrossRefGoogle Scholar
  51. 51.
    Bartel DP. (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell; 116:281–297.PubMedCrossRefGoogle Scholar
  52. 52.
    Du T, Zamore PD. (2005) microPrimer: the biogenesis and function of microRNA. Development; 132:4645–4652.PubMedCrossRefGoogle Scholar
  53. 53.
    Wienholds E, Plasterk RH. (2005) MicroRNA function in animal development. FEBS letters; 579:5911–5922.PubMedCrossRefGoogle Scholar
  54. 54.
    Houbaviy HB, Murray MF, Sharp PA. (2003) Embryonic stem cell-specific MicroRNAs. Developmental Cell; 5:351–358.PubMedCrossRefGoogle Scholar
  55. 55.
    Suh MR, Lee Y, Kim JY, et al. (2004) Human embryonic stem cells express a unique set of microRNAs. Developmental biology; 270:488–498.PubMedCrossRefGoogle Scholar
  56. 56.
    Johnston RJ, Hobert O. (2003) A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature; 426:845–849.PubMedCrossRefGoogle Scholar
  57. 57.
    Chang S, Johnston RJ, Jr., Frokjaer-Jensen C, Lockery S, Hobert O. (2004) MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature; 430:785–789.PubMedCrossRefGoogle Scholar
  58. 58.
    Giraldez AJ, Cinalli RM, Glasner ME, et al. (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science; 308:833–838.PubMedCrossRefGoogle Scholar
  59. 59.
    Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. (2006) Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem cells; 24:857–864.PubMedCrossRefGoogle Scholar
  60. 60.
    Smirnova L, Grafe A, Seiler A, et al. (2005) Regulation of miRNA expression during neural cell specification. The European journal of neuroscience; 21:1469–1477.PubMedCrossRefGoogle Scholar
  61. 61.
    Wu J, Xie X. (2006) Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome biology; 7:R85.PubMedCrossRefGoogle Scholar
  62. 62.
    Conaco C, Otto S, Han JJ, Mandel G. (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the United States of America; 103:2422–2427.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  1. 1.Division of Neurosciences, and Center for Gene Expression and Drug DiscoveryBeckman Research Institute of City of HopeDuarteUSA

Personalised recommendations