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Epigenetic mechanisms in neurogenesis

Key Points

  • DNA methylation and DNA methyltransferases regulate neurogenesis through epigenetic control of gene expression.

  • Dynamic DNA demethylation exerts temporal control over transcription control during neurogenesis.

  • Cytosine modification derivatives and ten-eleven translocation (TET) proteins precisely coordinate neurogenesis.

  • Histone modification dynamics and their regulators can exert a broad influence over neurogenic processes both directly and indirectly.

Abstract

In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms — including DNA and histone modifications, as well as regulation by non-coding RNAs — have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.

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Figure 1: Embryonic and adult neurogenesis.
Figure 2: Major forms of epigenetic modifications.

References

  1. 1

    Waddington, C. H. An Introduction to Modern Genetics (G. Allen & Unwin ltd., 1939). This is the first time that the term 'epigenetics' was proposed.

  2. 2

    Felsenfeld, G. A brief history of epigenetics. Cold Spring Harbor Persp. Biol. 6, a018200 (2014).

    Article  CAS  Google Scholar 

  3. 3

    Wu, H. & Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45–68 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Fu, Y., Dominissini, D., Rechavi, G. & He, C. Gene expression regulation mediated through reversible m6A RNA methylation. Nat. Rev. Genet. 15, 293–306 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Bond, A. M., Ming, G.-l. & Song, H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell 17, 385–395 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Ming, G. L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011). This review highlights the main principles of adult neurogenesis and summarizes the key remaining questions in the field.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Feliciano, D. M., Bordey, A. & Bonfanti, L. Noncanonical sites of adult neurogenesis in the mammalian brain. Cold Spring Harb. Perspect. Biol. 7, a018846 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Ma, D. K. et al. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat. Neurosci. 13, 1338–1344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hirabayashi, Y. & Gotoh, Y. Epigenetic control of neural precursor cell fate during development. Nat. Rev. Neurosci. 11, 377–388 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Gotz, M. & Huttner, W. B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788 (2005). This review is a comprehensive summary of the cell biology of embryonic and adult neurogenesis.

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Fishell, G. & Kriegstein, A. R. Neurons from radial glia: the consequences of asymmetric inheritance. Curr. Opin. Neurobiol. 13, 34–41 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Kriegstein, A. R. & Gotz, M. Radial glia diversity: a matter of cell fate. Glia 43, 37–43 (2003).

    Article  PubMed  Google Scholar 

  14. 14

    Noctor, S. C. et al. Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J. Neurosci. 22, 3161–3173 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Hartfuss, E., Galli, R., Heins, N. & Gotz, M. Characterization of CNS precursor subtypes and radial glia. Dev. Biol. 229, 15–30 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Kessaris, N., Pringle, N. & Richardson, W. D. Specification of CNS glia from neural stem cells in the embryonic neuroepithelium. Phil. Trans. R. Soc. B 363, 71–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009). This review systematically summarizes the current state of knowledge of embryonic and adult neurogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Urban, N. & Guillemot, F. Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front. Cell Neurosci. 8, 396 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Furutachi, S. et al. Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. Nat. Neurosci. 18, 657–665 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Fuentealba, L. C. et al. Embryonic origin of postnatal neural stem cells. Cell 161, 1644–1655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sun, G. J. et al. Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation. Nat. Neurosci. 18, 1722–1724 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Alvarez-Buylla, A., Garcia-Verdugo, J. M. & Tramontin, A. D. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Cameron, H. A. & McKay, R. D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Christian, K. M., Song, H. & Ming, G. L. Functions and dysfunctions of adult hippocampal neurogenesis. Annu. Rev. Neurosci. 37, 243–262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Bird, A. P. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986). This review highlights the key role of CpG islands and their relation to DNA methylation.

    Article  CAS  Google Scholar 

  27. 27

    Guo, J. U. et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat. Neurosci. 14, 1345–1351 (2011). This study is the first systematic analysis of genome-wide CpG methylation changes following neuronal activation in the adult mammalian brain and discusses its potentially unique role in neuronal functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Bestor, T. H. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9, 2395–2402 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Goto, K. et al. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 56, 39–44 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Feng, J., Chang, H., Li, E. & Fan, G. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J. Neurosci. Res. 79, 734–746 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    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).

    Article  CAS  PubMed  Google Scholar 

  32. 32

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

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Fan, G. et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345–3356 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Nguyen, S., Meletis, K., Fu, D., Jhaveri, S. & Jaenisch, R. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev. Dyn. 236, 1663–1676 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Wu, H. et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444–448 (2010). This study uses Dnmt3a -conditional-knockout mice to reveal its critical role in neurogenesis through crosstalk with the repressive histone modification H3K27me3 and its modifiers, the PcG proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Martins-Taylor, K., Schroeder, D. I., LaSalle, J. M., Lalande, M. & Xu, R. H. Role of DNMT3B in the regulation of early neural and neural crest specifiers. Epigenetics 7, 71–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Yoder, J. A., Soman, N. S., Verdine, G. L. & Bestor, T. H. DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J. Mol. Biol. 270, 385–395 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Guo, J. U. et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat. Neurosci. 17, 215–222 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013). References 38 and 39 describe non-canonical CpH methylation in the mammalian genome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Chen, L. et al. MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc. Natl Acad. Sci. USA 112, 5509–5514 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Mo, A. et al. Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 86, 1369–1384 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Zhao, X. et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl Acad. Sci. USA 100, 6777–6782 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Li, X. et al. Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. J. Biol. Chem. 283, 27644–27652 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lewis, J. D. et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Mellen, M., Ayata, P., Dewell, S., Kriaucionis, S. & Heintz, N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012). This study isolates and profiles the global epigenome and transcriptome of Purkinje cells, granule cells and Bergmann glia from the mouse cerebellum.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Smrt, R. D. et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol. Dis. 27, 77–89 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302, 890–893 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Faigle, R. & Song, H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim. Biophys. Acta 1830, 2435–2448 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009). This study, for the first time, identifies TET1 as a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyses the conversion of 5mC to 5hmC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011). References 54 and 55 together reveal that TET proteins can further convert 5hmC to 5fC and then 5caC, with the latter being converted back to cytosine by thymine DNA glycosylase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Guo, J. U., Su, Y., Zhong, C., Ming, G. L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423–434 (2011). This study reveals that TET1 initiates DNA demethylation followed by DNA repair and thus controls key neuronal gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ma, D. K. et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074–1077 (2009). This study reveals that DNA demethylation plays a crucial part in controlling key neuronal gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    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 

  59. 59

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

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Shin, J., Ming, G. L. & Song, H. Decoding neural transcriptomes and epigenomes via high-throughput sequencing. Nat. Neurosci. 17, 1463–1475 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Hahn, M. A. et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep. 3, 291–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Szulwach, K. E. et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat. Neurosci. 14, 1607–1616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Song, C. X. et al. Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153, 678–691 (2013). This study develops a genome-wide approach to specifically map 5fC-containing DNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Yu, M. et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149, 1368–1380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Bachman, M. et al. 5-Formylcytosine can be a stable DNA modification in mammals. Nat. Chem. Biol. 11, 555–557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013). This study reveals a range of 5hmC-binding proteins and their differential functions in ES cells and NSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Pichler, G. et al. Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways. J. Cell. Biochem. 112, 2585–2593 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Huang, Y. et al. Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 111, 1361–1366 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Zhang, R. R. et al. Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13, 237–245 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Xu, Y. et al. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151, 1200–1213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Hsieh, J. & Eisch, A. J. Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind. Neurobiol. Dis. 39, 73–84 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Wang, F. et al. Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease. Hum. Mol. Genet. 22, 3641–3653 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Riccio, A. Dynamic epigenetic regulation in neurons: enzymes, stimuli and signaling pathways. Nat. Neurosci. 13, 1330–1337 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Thomas, T. & Voss, A. K. Querkopf, a histone acetyltransferase, is essential for embryonic neurogenesis. Front. Biosci. 9, 24–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Schwartz, Y. B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nat. Rev. Genet. 8, 9–22 (2007). This is a comprehensive review summarizing the function of Polycomb proteins.

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Schuettengruber, B., Martinez, A. M., Iovino, N. & Cavalli, G. Trithorax group proteins: switching genes on and keeping them active. Nat. Rev. Mol. Cell Biol. 12, 799–814 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Hirabayashi, Y. et al. Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63, 600–613 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Pereira, J. D. et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc. Natl Acad. Sci. USA 107, 15957–15962 (2010).

    Article  PubMed  Google Scholar 

  80. 80

    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 

  81. 81

    Lim, D. A. et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458, 529–533 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    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 

  83. 83

    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).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Sun, G. et al. Histone demethylase LSD1 regulates neural stem cell proliferation. Mol. Cell. Biol. 30, 1997–2005 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Laurent, B. et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol. Cell 57, 957–970 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    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 

  87. 87

    Yang, X. J. & Seto, E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26, 5310–5318 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Merson, T. D. et al. The transcriptional coactivator Querkopf controls adult neurogenesis. J. Neurosci. 26, 11359–11370 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    MacDonald, J. L. & Roskams, A. J. Histone deacetylases 1 and 2 are expressed at distinct stages of neuro-glial development. Dev. Dyn. 237, 2256–2267 (2008).

    Article  PubMed  Google Scholar 

  90. 90

    Sun, G., Yu, R. T., Evans, R. M. & Shi, Y. Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc. Natl Acad. Sci. USA 104, 15282–15287 (2007).

    Article  PubMed  Google Scholar 

  91. 91

    Gallagher, D. et al. Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. Dev. Cell 32, 31–42 (2015). This study shows that the chromatin modifier ANKRD11 can coordinate with HDAC3 to modulate adult neurogenesis and links its dysregulation to autism spectrum disorders.

    Article  CAS  PubMed  Google Scholar 

  92. 92

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    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  Google Scholar 

  94. 94

    Xiong, Y. & Guan, K. L. Mechanistic insights into the regulation of metabolic enzymes by acetylation. J. Cell Biol. 198, 155–164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Winner, B. & Winkler, J. Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 7, a021287 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Hoglinger, G. U. et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat. Neurosci. 7, 726–735 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Nuber, S. et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease. J. Neurosci. 28, 2471–2484 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Melrose, H. L. et al. Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis. 40, 503–517 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123, 383–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Winner, B. et al. Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J. Neurosci. 32, 16906–16916 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Jowaed, A., Schmitt, I., Kaut, O. & Wullner, U. Methylation regulates α-synuclein expression and is decreased in Parkinson's disease patients' brains. J. Neurosci. 30, 6355–6359 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Matsumoto, L. et al. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease. PLoS ONE 5, e15522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Desplats, P. et al. α-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J. Biol. Chem. 286, 9031–9037 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Winner, B. et al. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis. 41, 706–716 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Beccano-Kelly, D. A. et al. LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Hum. Mol. Genet. 24, 1336–1349 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Cho, H. J. et al. MicroRNA-205 regulates the expression of Parkinson's disease-related leucine-rich repeat kinase 2 protein. Hum. Mol. Genet. 22, 608–620 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Chouraki, V. & Seshadri, S. Genetics of Alzheimer's disease. Adv. Genet. 87, 245–294 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Kamboh, M. I. Molecular genetics of late-onset Alzheimer's disease. Ann. Hum. Genet. 68, 381–404 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  113. 113

    Coppieters, N. & Dragunow, M. Epigenetics in Alzheimer's disease: a focus on DNA modifications. Curr. Pharm. Des. 17, 3398–3412 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Chouliaras, L. et al. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients. Neurobiol. Aging 34, 2091–2099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    De Jager, P. L. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat. Neurosci. 17, 1156–1163 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Handler, M., Yang, X. & Shen, J. Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 127, 2593–2606 (2000).

    CAS  PubMed  Google Scholar 

  117. 117

    Bonds, J. A. et al. Presenilin-1 dependent neurogenesis regulates hippocampal learning and memory. PLoS ONE 10, e0131266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Kumar, A. & Thakur, M. K. Epigenetic regulation of presenilin 1 and 2 in the cerebral cortex of mice during development. Dev. Neurobiol. 75, 1165–1173 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Li, G. et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5, 634–645 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Yu, C. E. et al. Epigenetic signature and enhancer activity of the human APOE gene. Hum. Mol. Genet. 22, 5036–5047 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    MacDonald, M. E. et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  122. 122

    Martindale, D. et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat. Genet. 18, 150–154 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Phillips, W., Morton, A. J. & Barker, R. A. Abnormalities of neurogenesis in the R6/2 mouse model of Huntington's disease are attributable to the in vivo microenvironment. J. Neurosci. 25, 11564–11576 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Lazic, S. E. et al. Decreased hippocampal cell proliferation in R6/1 Huntington's mice. Neuroreport 15, 811–813 (2004).

    Article  PubMed  Google Scholar 

  125. 125

    Kohl, Z. et al. Impaired adult olfactory bulb neurogenesis in the R6/2 mouse model of Huntington's disease. BMC Neurosci. 11, 114 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Valor, L. M. & Guiretti, D. What's wrong with epigenetics in Huntington's disease? Neuropharmacology 80, 103–114 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Gorbunova, V., Seluanov, A., Mittelman, D. & Wilson, J. H. Genome-wide demethylation destabilizes CTG·CAG trinucleotide repeats in mammalian cells. Hum. Mol. Genet. 13, 2979–2989 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Ratovitski, T. et al. Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle 11, 2006–2021 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Shirasaki, D. I. et al. Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75, 41–57 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Ng, C. W. et al. Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc. Natl Acad. Sci. USA 110, 2354–2359 (2013).

    Article  PubMed  Google Scholar 

  131. 131

    Schoenfeld, T. J. & Cameron, H. A. Adult neurogenesis and mental illness. Neuropsychopharmacology 40, 113–128 (2015).

    Article  PubMed  Google Scholar 

  132. 132

    DeCarolis, N. A. & Eisch, A. J. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58, 884–893 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Jun, H., Mohammed Qasim Hussaini, S., Rigby, M. J. & Jang, M. H. Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders. Neural Plast. 2012, 854285 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Petrik, D., Lagace, D. C. & Eisch, A. J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21–34 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Taliaz, D., Stall, N., Dar, D. E. & Zangen, A. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol. Psychiatry 15, 80–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Abuhatzira, L., Makedonski, K., Kaufman, Y., Razin, A. & Shemer, R. MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 2, 214–222 (2007).

    Article  PubMed  Google Scholar 

  139. 139

    Klein, M. E. et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513–1514 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Larimore, J. L. et al. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol. Dis. 34, 199–211 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Li, W. & Pozzo-Miller, L. BDNF deregulation in Rett syndrome. Neuropharmacology 76, 737–746 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Pohodich, A. E. & Zoghbi, H. Y. Rett syndrome: disruption of epigenetic control of postnatal neurological functions. Hum. Mol. Genet. 24, R10–R16 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Li, H. et al. Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway. Nat. Commun. 5, 5601 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Brunet-Gouet, E. & Decety, J. Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res. 148, 75–92 (2006).

    Article  PubMed  Google Scholar 

  146. 146

    Reif, A. et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 11, 514–522 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Akbarian, S. Epigenetic mechanisms in schizophrenia. Dialogues Clin. Neurosci. 16, 405–417 (2014).

    PubMed  PubMed Central  Google Scholar 

  148. 148

    Ikegame, T. et al. DNA methylation of the BDNF gene and its relevance to psychiatric disorders. J. Hum. Genet. 58, 434–438 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Auta, J. et al. DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients. Schizophr Res. 150, 312–318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Gavin, D. P., Kartan, S., Chase, K., Jayaraman, S. & Sharma, R. P. Histone deacetylase inhibitors and candidate gene expression: an in vivo and in vitro approach to studying chromatin remodeling in a clinical population. J. Psychiatr. Res. 43, 870–876 (2009).

    Article  PubMed  Google Scholar 

  151. 151

    Aberg, K. A. et al. Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry 71, 255–264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Hannon, E. et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat. Neurosci. 19, 48–54 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Jaffe, A. E. et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat. Neurosci. 19, 40–47 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Li, X. & Jin, P. Roles of small regulatory RNAs in determining neuronal identity. Nat. Rev. Neurosci. 11, 329–338 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    Clark, B. S. & Blackshaw, S. Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease. Front. Genet. 5, 164 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Gonzales-Roybal, G. & Lim, D. A. Chromatin-based epigenetics of adult subventricular zone neural stem cells. Front. Genet. 4, 194 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Jia, G., Fu, Y. & He, C. Reversible RNA adenosine methylation in biological regulation. Trends Genet. 29, 108–115 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Yue, Y., Liu, J. & He, C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29, 1343–1355 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Amiri, A. et al. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J. Neurosci. 32, 5880–5890 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Bian, S. et al. MicroRNA cluster miR-17-92 regulates neural stem cell expansion and transition to intermediate progenitors in the developing mouse neocortex. Cell Rep. 3, 1398–1406 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Dajas-Bailador, F. et al. microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons. Nat. Neurosci. 15, 697–699 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. 162

    Zhao, C., Sun, G., Li, S. & Shi, Y. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat. Struct. Mol. Biol. 16, 365–371 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Sun, G. et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat. Commun. 2, 529 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Zhao, C. et al. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc. Natl Acad. Sci. USA 107, 1876–1881 (2010).

    Article  PubMed  Google Scholar 

  165. 165

    Liu, C. et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6, 433–444 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Cheng, L. C., Pastrana, E., Tavazoie, M. & Doetsch, F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat. Neurosci. 12, 399–408 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Flynn, R. A. & Chang, H. Y. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell 14, 752–761 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Bond, A. M. et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat. Neurosci. 12, 1020–1027 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Ramos, A. D. et al. Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell 12, 616–628 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Meyer, K. D. & Jaffrey, S. R. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat. Rev. Mol. Cell Biol. 15, 313–326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Geula, S. et al. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347, 1002–1006 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    Bokar, J. A., Shambaugh, M. E., Polayes, D., Matera, A. G. & Rottman, F. M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3, 1233–1247 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Bokar, J. A., Rath-Shambaugh, M. E., Ludwiczak, R., Narayan, P. & Rottman, F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J. Biol. Chem. 269, 17697–17704 (1994).

    CAS  PubMed  Google Scholar 

  175. 175

    Liu, J. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93–95 (2014).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Ping, X.-L. et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24, 177–189 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Wang, Y. et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 16, 191–198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011). This study, for the first time, identifies fat mass and obesity-associated protein (FTO) as an RNA N6-methyladenosine demethylase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions. Nature 518, 560–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Alarcon, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported by the US National Institutes of Health (NIH; NS047344 and HD086820 to H.S., NS048271, NS095348, MH110160 and MH105128 to G.L.M., NS051630, NS079625 and MH102690 to P.J.), Dr. Miriam & Sheldon G. Adelson Medical Research Foundation (to G.L.M.) and the Howard Hughes Medical Institute (to C.H.). The authors apologize to colleagues whose work was not cited owing to space limitations.

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Correspondence to Hongjun Song.

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Glossary

Neural progenitor cells

(NPCs). Precursor cells of the nervous system that can produce more of themselves and differentiate into various types of neural cells.

Radial glial cells

(RGCs). Bipolar cells derived from neuroepithelial cells during embryonic stages that primarily serve as neural progenitor cells during embryonic neurogenesis.

Imprinted gene silencing

A subset of genes that display a parental-specific expression pattern. Compared with normal genes, for which both paternal and maternal alleles are expressed, imprinted genes only express one parental allele. The silencing of one imprinted allele is often mediated by epigenetic mechanisms, such as DNA methylation.

X-inactivation

Females carry two copies of the X chromosome and therefore could potentially express toxic levels (a 'double dose') of X chromosome-linked genes. To prevent this scenario, cells of an early female embryo will randomly inactivate one of the two X chromosomes for gene dosage compensation, termed X-inactivation.

TET family proteins

Ten-eleven translocation (TET) proteins serve as methylcytosine dioxygenases to convert 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in an iron-dependent manner.

DNA demethylation

An active biochemical process that removes a methyl group from cytosine; this process is catalysed by methylcytosine dioxygenases, such as ten-eleven translocation (TET) proteins.

Poised enhancers

Enhancers refer to the genomic regions that are characterized by uniquely bound transcription factors such as P300 and signature histone modifications such as histone H3 lysine 4 methylation (H3K4me1) that could potentially modulate transcription activation. Poised enhancers bear enhancer characteristics, but their functions are hampered by repressive chromatin marks such that they require additional cues to unleash their functions.

Transcriptome landscape

Global signature transcriptional patterns of different cell types. Maintaining cell type-specific gene expression is crucial for cell identity.

Interactomes

Whole sets of molecules that physically interact with given molecules. In this article, interactome specifically refers to protein–protein interactions.

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Yao, B., Christian, K., He, C. et al. Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci 17, 537–549 (2016). https://doi.org/10.1038/nrn.2016.70

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