We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

DNA methylation dynamics in neurogenesis

    Zhiqin Wang

    Department of Human Genetics, Emory University, Atlanta, GA 30322, USA

    Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China

    ,
    Beisha Tang

    Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China

    ,
    Yuquan He

    Department of Cardiology, The Third Affiliated Hospital of Jilin University, Jilin University, Changchun, Jilin, PR China

    &
    Peng Jin

    *Author for correspondence:

    E-mail Address: peng.jin@emory.edu

    Department of Human Genetics, Emory University, Atlanta, GA 30322, USA

    Published Online:https://doi.org/10.2217/epi.15.119

    Neurogenesis is not limited to the embryonic stage, but continually proceeds in the adult brain throughout life. Epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNA, play important roles in neurogenesis. For decades, DNA methylation was thought to be a stable modification, except for demethylation in the early embryo. In recent years, DNA methylation has proved to be dynamic during development. In this review, we summarize the latest understanding about DNA methylation dynamics in neurogenesis, including the roles of different methylation forms (5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine), as well as their ‘writers’, ‘readers’ and interactions with histone modifications.

    References

    • 1 Taverna E, Gotz M, Huttner WB. The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annu. Rev. Cell Dev. Biol. 30, 465–502 (2014).
    • 2 Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4), 687–702 (2011).
    • 3 Russo VEA, Martienssen RA, Riggs AD et al. Epigenetic Mechanisms of Gene Regulation. Russo VEA, Martienssen RA, Riggs AD (Eds). Cold Spring Harbor Laboratory Press, Woodbury, NY, USA (1996).
    • 4 Bird A. Perceptions of epigenetics. Nature 447(7143), 396–398 (2007).
    • 5 Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324(5929), 929–930 (2009).
    • 6 Tahiliani M, Koh KP, Shen Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929), 930–935 (2009).
    • 7 Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466(7310), 1129–1133 (2010).
    • 8 Ficz G, Branco MR, Seisenberger S et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473(7347), 398–402 (2011).
    • 9 He YF, Li BZ, Li Z et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333(6047), 1303–1307 (2011).
    • 10 Ito S, Shen L, Dai Q et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047), 1300–1303 (2011).
    • 11 Pastor WA, Pape UJ, Huang Y et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473(7347), 394–397 (2011).
    • 12 Meissner A, Mikkelsen TS, Gu H et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205), 766–770 (2008).
    • 13 Siegel A, Sapru HN. Essential Neuroscience. Wolters Kluwer, MD, PA, USA, 19–32 (2015).
    • 14 Gotz M, Huttner WB. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6(10), 777–788 (2005).
    • 15 Gotz M, Barde YA. Radial glial cells defined and major intermediates between embryonic stem cells and CNS neurons. Neuron 46(3), 369–372 (2005).
    • 16 Mori T, Buffo A, Gotz M. The novel roles of glial cells revisited: the contribution of radial glia and astrocytes to neurogenesis. Curr. Top. Dev. Biol. 69, 67–99 (2005).
    • 17 Qian X, Shen Q, Goderie SK et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28(1), 69–80 (2000).
    • 18 Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8(6), 427–437 (2007).
    • 19 Sauvageot CM, Stiles CD. Molecular mechanisms controlling cortical gliogenesis. Curr. Opin. Neurobiol. 12(3), 244–249 (2002).
    • 20 Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009).
    • 21 Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394), U376–U381 (2012).
    • 22 Suzuki IK, Vanderhaeghen P. Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells. Development 142(18), 3138–3150 (2015).
    • 23 Rakic P. A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends Neurosci. 18(9), 383–388 (1995).
    • 24 Zappaterra MW, Lehtinen MK. The cerebrospinal fluid: regulator of neurogenesis, behavior, and beyond. Cell. Mol. Life Sci. 69(17), 2863–2878 (2012).
    • 25 Zhang X, Huang CT, Chen J et al. Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 7(1), 90–100 (2010).
    • 26 Hamby ME, Coskun V, Sun YE. Transcriptional regulation of neuronal differentiation: the epigenetic layer of complexity. Biochim. Biophys. Acta 1779(8), 432–437 (2008).
    • 27 Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121(4), 645–657 (2005).
    • 28 Codega P, Silva-Vargas V, Paul A et al. Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron 82(3), 545–559 (2014).
    • 29 Lazarini F, Lledo PM. Is adult neurogenesis essential for olfaction? Trends Neurosci. 34(1), 20–30 (2011).
    • 30 Aimone JB, Deng W, Gage FH. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70(4), 589–596 (2011).
    • 31 Bergmann O, Spalding KL, Frisen J. Adult neurogenesis in humans. Cold Spring Harb. Perspect. Biol. 7(7), a018994 (2015).
    • 32 Spalding KL, Bergmann O, Alkass K et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153(6), 1219–1227 (2013).
    • 33 Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R. Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. J. Neurosci. 30(9), 3489–3498 (2010).
    • 34 Pierfelice T, Alberi L, Gaiano N. Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69(5), 840–855 (2011).
    • 35 Nam HS, Benezra R. High levels of Id1 expression define B1 type adult neural stem cells. Cell Stem Cell 5(5), 515–526 (2009).
    • 36 Lim DA, Huang YC, Swigut T et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458(7237), 529–533 (2009).
    • 37 Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 386(6624), 493–495 (1997).
    • 38 Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature 415(6875), 1030–1034 (2002).
    • 39 Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat. Neurosci. 13(11), 1338–1344 (2010).
    • 40 Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 11(3), 204–220 (2010).
    • 41 Lee HJ, Hore TA, Reik W. Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14(6), 710–719 (2014).
    • 42 Lister R, Mukamel EA, Nery JR et al. Global epigenomic reconfiguration during mammalian brain development. Science 341(6146), 1237905 (2013).
    • 43 Shirane K, Toh H, Kobayashi H et al. Mouse oocyte methylomes at base resolution reveal genome-wide accumulation of non-CpG methylation and role of DNA methyltransferases. PLoS Genet. 9(4), e1003439 (2013).
    • 44 Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet. 19(3), 219–220 (1998).
    • 45 Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3), 247–257 (1999).
    • 46 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).
    • 47 Bestor TH. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9(16), 2395–2402 (2000).
    • 48 Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317(5845), 1760–1764 (2007).
    • 49 Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14(3), 204–220 (2013).
    • 50 Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr. Opin. Genet. Dev. 3(2), 226–231 (1993).
    • 51 Defossez PA, Stancheva I. Biological functions of methyl-CpG-binding proteins. Prog. Mol. Biol. Transl. Sci. 101, 377–398 (2011).
    • 52 Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 16(1), 6–21 (2002).
    • 53 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature 403(6769), 501–502 (2000).
    • 54 Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1–2), 45–68 (2014).
    • 55 Maiti A, Drohat AC. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine potential implications for active demethylation of CpG sites. J. Biol. Chem. 286(41), 35334–35338 (2011).
    • 56 Gu TP, Guo F, Yang H et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477(7366), 606–610 (2011).
    • 57 Inoue A, Shen L, Dai Q, He C, Zhang Y. Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res. 21(12), 1670–1676 (2011).
    • 58 Iqbal K, Jin SG, Pfeifer GP, Szabo PE. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc. Natl Acad. Sci. USA 108(9), 3642–3647 (2011).
    • 59 Santos F, Peat J, Burgess H, Rada C, Reik W, Dean W. Active demethylation in mouse zygotes involves cytosine deamination and base excision repair. Epigenet. Chromatin 6(1), 39 (2013).
    • 60 Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 14(6), 341–356 (2013).
    • 61 Goto K, Numata M, Komura JI, Ono T, Bestor TH, Kondo H. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 56(1–2), 39–44 (1994).
    • 62 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(6), 734–746 (2005).
    • 63 Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6), 915–926 (1992).
    • 64 Fan G, Beard C, Chen RZ et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21(3), 788–797 (2001).
    • 65 Rhee KD, Yu J, Zhao CY, Fan G, Yang XJ. Dnmt1-dependent DNA methylation is essential for photoreceptor terminal differentiation and retinal neuron survival. Cell Death Dis. 3, e427 (2012).
    • 66 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(6), 1663–1676 (2007).
    • 67 Tan L, Xiong L, Xu W et al. Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hMeDIP-seq method. Nucleic Acids Res. 41(7), e84 (2013).
    • 68 Wang Y, Zhang Y. Regulation of TET protein stability by calpains. Cell Rep. 6(2), 278–284 (2014).
    • 69 Li T, Yang D, Li J, Tang Y, Yang J, Le W. Critical role of Tet3 in neural progenitor cell maintenance and terminal differentiation. Mol. Neurobiol. 51(1), 142–154 (2015).
    • 70 Hahn MA, Qiu R, Wu X et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep. 3(2), 291–300 (2013).
    • 71 Dawlaty MM, Ganz K, Powell BE et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9(2), 166–175 (2011).
    • 72 Dawlaty MM, Breiling A, Le T et al. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev. Cell 24(3), 310–323 (2013).
    • 73 Zhang RR, Cui QY, Murai K et al. Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13(2), 237–245 (2013).
    • 74 Rudenko A, Dawlaty MM, Seo J et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79(6), 1109–1122 (2013).
    • 75 Kaas GA, Zhong C, Eason DE et al. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79(6), 1086–1093 (2013).
    • 76 Xu Y, Xu C, Kato A et al. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151(6), 1200–1213 (2012).
    • 77 Ma DK, Jang MH, Guo JU et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323(5917), 1074–1077 (2009).
    • 78 Guo JU, Su YJ, Zhong C, Ming GL, Song HJ. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145(3), 423–434 (2011).
    • 79 Stadler MB, Murr R, Burger L et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480(7378), 490–495 (2011).
    • 80 Yu M, Hon GC, Szulwach KE et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149(6), 1368–1380 (2012).
    • 81 Etchegaray JP, Chavez L, Huang Y et al. The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat. Cell Biol. 17(5), 545–557 (2015).
    • 82 Spruijt CG, Gnerlich F, Smits AH et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152(5), 1146–1159 (2013).
    • 83 Colquitt BM, Allen WE, Barnea G, Lomvardas S. Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity. Proc. Natl Acad. Sci. USA 110(36), 14682–14687 (2013).
    • 84 Cortazar D, Kunz C, Selfridge J et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470(7334), 419–423 (2011).
    • 85 Wheldon LM, Abakir A, Ferjentsik Z et al. Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells. Cell. Rep. 7(5), 1353–1361 (2014).
    • 86 Takizawa T, Nakashima K, Namihira M et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev. Cell 1(6), 749–758 (2001).
    • 87 Fan G, Martinowich K, Chin MH et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK–STAT signaling. Development 132(15), 3345–3356 (2005).
    • 88 Namihira M, Kohyama J, Semi K et al. Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev. Cell 16(2), 245–255 (2009).
    • 89 Wu H, Coskun V, Tao J et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329(5990), 444–448 (2010).
    • 90 Zhao XY, Ueba T, Christie BR et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl Acad. Sci. USA 100(11), 6777–6782 (2003).
    • 91 Liu C, Teng ZQ, Santistevan NJ et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6(5), 433–444 (2010).
    • 92 Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A. Increased neurogenesis in a model of electroconvulsive therapy. Biol. Psychiatry 47(12), 1043–1049 (2000).
    • 93 Mo A, Mukamel EA, Davis FP et al. Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 86(6), 1369–1384 (2015).
    • 94 Wion D, Casadesus J. N6-methyl-adenine: an epigenetic signal for DNA–protein interactions. Nat. Rev. Microbiol. 4(3), 183–192 (2006).
    • 95 Fu Y, Luo GZ, Chen K et al. N6-methyldeoxyadenosine marks active transcription start sites in Chlamydomonas. Cell 161(4), 879–892 (2015).
    • 96 Greer EL, Blanco MA, Gu L et al. DNA Methylation on N6-adenine in C. elegans. Cell 161(4), 868–878 (2015).
    • 97 Zhang G, Huang H, Liu D et al. N6-methyladenine DNA modification in Drosophila. Cell 161(4), 893–906 (2015).