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Home arrow Health arrow DNA Modifications in the Brain. Neuroepigenetic Regulation of Gene Expression


DNA methylation, for a long time regarded as a stable DNA modification that controls cellular differentiation, is now widely accepted to be dynamically regulated in the nervous system and plays an essential role in memory formation and adaptation to an ever-changing environment. Dynamic changes in DNA methylation occur in postmitotic neurons; the methylation-mediated chromatin remodeling may play critical roles in gene expression modulation involved in long-lasting neuronal responses. DNA methylation represents one of the most permanent mechanisms of cellular memory. In support of this view, most differentiated cells have a rather small activity of DNMTs. Although the mature brain consists mainly of terminally differentiated postmitotic cells, surprisingly, high levels of DNA methylation and demethylation activities persist throughout the whole life.


This work was supported by Russian Science Foundation grant no. 14-50-00029.


Ashapkin, V V., Antoniv, T. T., & Vanyushin, B. F. (1995). Methylation-dependent binding of wheat nuclear proteins to promoter region of ribosomal RNA genes. Gene, 157, 273-277.

Ashapkin, V V., Romanov, G. A., Tushmalova, N. A., & Vanyushin, B. F. (1983). Selective synthesis of DNA in the rat brain induced by learning. Biokhimiya, 48, 355-362.

Barreto, G., Schafer, A., Marhold, J., Stach, D., Swaminathan, S. K., Handa,V, et al. (2007). Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature, 445, 671-675.

Bashkite, E. A., Kirnos, M. D., Kiryanov, G. I., Aleksandrushkina, N. I., & Vanyushin, B. F. (1980). Replication and methylation of DNA in tobacco cell suspension culture and the influence of auxin. Biokhimiya, 45, 1448-1456.

Berdyshev, G. D., Korotaev, G. K., Boyarskikh, G. V., & Vanyushin, B. F. (1967). Nucleotide composition of DNA and RNA from somatic tissues of humpback salmon and its changes during spawning. Biokhimiya, 32, 988-993.

Bestor, T., Laudano, A., Mattaliano, R., & Ingram, V (1988). Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells: the carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. Journal of Molecular Biology, 203, 971-983.

Bhattacharya, S. K., Ramchandani, S., Cervoni, N., & Szyf, M. (1999). A mammalian protein with specific demethylase activity for mCpG DNA. Nature, 391, 579-583.

Champagne, F, Weaver, I., Diorio, J., Dymov, S., Szyf, M., & Meaney, M. J. (2006). Maternal care associated with methylation of the estrogen receptor-a1b promoter and estrogen receptor- a expression in the medial preoptic area of female offspring. Endocrinology, 141, 2909-2915.

Clark, S. J., Harrison, J., & Frommer, M. (1995). CpNpG methylation in mammalian cells. Nature Genetics, 10, 20-27.

Cortellino, S., Xu, J., Sannai, M., Moore, R., Caretti, E., Cigliano, A., et al. (2011). Thymine DNA glycosyl- ase is essential for active DNA demethylation by linked deamination-base excision repair. Cell, 146, 67-79.

Culp, L. A., Dore, E., & Brown, G. M. (1970). Methylated bases in DNA of animal origin. Archives of Biochemistry and Biophysics, 136, 73-79.

Doskocil, J., & Sorm, F (1962). Distribution of 5-methylcytosine in pyrimidine sequences of deoxyribonucleic acids. Biochimica et Biophysica Acta, 55, 953-959.

Dunn, D. B., & Smith, J. D. (1955). Occurrence of a new base in the deoxyribonucleic acid of a strain of

Bacterium coli. Nature, 115, 336-337.

Fan, G., Beard, C., Chen, R. Z., Csankovszki, G., Sun, Y., Siniaia, M., et al. (2001). DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 21, 788-797.

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, 19, 734-746.

Feng, J., Zhou, Y., Campbell, S. L., Le, T., Li, E., Sweatt, J. D., et al. (2010). Dnmt1 and Dnmt3a are required for the maintenance of DNA methylation and synaptic function in adult forebrain neurons. Nature Neuroscience, 13, 423-430.

Florath, I., Butterbach, K., Muller, H., Bewerunge-Hudler, M., & Brenner, H. (2014). Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Human Molecular Genetics, 23, 1186-1201.

Fremont, M., Siegmann, M., Gaulis, S., Matthies, R., Hess, D., & Jost, J.-P. (1997). Demethylation of DNA by purified chick embryo 5-methylcytosine-DNA glycosylase requires both protein and RNA. Nucleic Acids Research, 25, 2375-2380.

Gold, M., & Hurwitz, J. (1963). The enzymatic methylation of the nucleic acids. Cold Spring Harbour Symposia of Quantitative Biology, 28, 149-156.

Gong, Z., & Zhu, J.-K. (2011). Active DNA demethylation by oxidation and repair. Cell Research, 21, 1649-1651.

Goto, K., Numata, M., Komura, J.-I., Ono, T., Bestor, T. H., & Kondo, H. (1994). Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation, 56, 39-44.

Gowher, H., Leismann, O., & Jeltsch, A. (2000). DNA of Drosophila melanogaster contains 5-methylcytosine.

EMBO Journal, 19, 6918-6923.

Grippo, P., Iaccarino, M., Parisi, E., & Scarano, E. (1968). Methylation of DNA in developing sea urchin embryos. Journal of Molecular Biology, 36, 195-208.

Gruenbaum, Y., Naveh-Many, T., Cedar, H., & Razin, A. (1981). Sequence specificity of methylation in higher plant DNA. Nature, 292, 860-862.

Gruenbaum, Y, Stein, R., Cedar, H., & Razin, A. (1981). Methylation of CpG sequences in eukaryotic DNA. FEBS Letters, 124, 67-71.

Guo, J. U., Ma, D. K., Mo, H., Ball, M. P., Jang, M.-H., Bonaguidi, M. A., et al. (2011). Neuronal activity modifies DNA methylation landscape in the adult brain. Nature Neuroscience, 14, 1345—1351.

Guo, J. U., Su, Y, Shin, J. H., Shin, J., Li, H., Xie, B., et al. (2014). Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nature Neuroscience, 17, 215—222.

Guskova, L. V., Burtseva, N. N., Tushmalova, N. A., & Vaniushin, B. F. (1977). Level of methylated nuclear DNA in neurons and glia of rat cerebral cortex and its alteration upon elaboration of a conditioned reflex. Doklady Akademii Nauk SSSR, 233, 993—996.

Gustems, M., Woellmer, A., Rothbauer, U., Eck, S. H., Wieland, T., Lutter, D., et al. (2014). c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs.

Nucleic Acids Research, 42, 3059—3072.

Hamm, S., Just, G., Lacoste, N., Moitessier, N., Szyf, M., & Mamer, O. (2008). On the mechanism of demeth- ylation of 5-methylcytosine in DNA. Bioorganic & Medicinal Chemistry Letters, 18, 1046—1049.

He, Y.-F., Li, B.-Z., Li, Z., Liu, P, Wang, Y, Tang, Q., et al. (2011). Tet-mediated formation of 5-carboxylcy- tosine and its excision by TDG in mammalian DNA. Science, 333, 1303—1307.

Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V A., & Bird, A. (2001). Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes & Development, 15, 710—723.

Holliday, R., & Pugh, J. E. (1975). DNA modification mechanisms and gene activity during development. Science, 187, 226—232.

Hotchkiss, R. D. (1948). The quantitative separation of purines, pyrimidines and nucleosides by paper chromatography. The Journal of Biological Chemistry, 175, 315—332.

Jeltsch, A., Nellen, W., & Lyko, F. (2006). Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends in Biochemical Sciences, 31, 306—308.

Jones, P. A. (2012). Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics, 13, 484-492.

Jost, J.-P (1993). Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proceedings of the National Academy of Sciences of the United States of America, 90, 4684—4688.

Jost, J.-P., Fremont, M., Siegmann, M., & Hofsteenge, J. (1997). The RNA moiety of chick embryo 5-meth- ylcytosine-DNA glycosylase targets DNA demethylation. Nucleic Acids Research, 25, 4545-4550.

Jost, J.-P., Siegmann, M., Sun, L., & Leung, R. (1995). Mechanism of DNA demethylation in chicken embryos. The Journal of Biological Chemistry, 370, 9734-9739.

Kirnos, M. D., Aleksandrushkina, N. I., & Vanyushin, B. F. (1981). 5-Methylcytosine in pyrimidine sequences of plant and animal DNA: specificity of methylation. Biokhimiya, 46, 1458-1474.

Kiryanov, G. I., Kirnos, M. D., Demidkina, N. P., Alexandrushkina, N. I., & Vanyushin, B. F. (1980). Methylation of DNA in L cells on replication. FEBS Letters, 112, 225-228.

Kriaucionis, S., & Heintz, N. (2009). The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science, 324, 929-930.

Leach, P T., Poplawski, S. G., Kenney, J. W., Hoffman, B., Liebermann, D. A., Abel, T., et al. (2012). Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learning & Memory, 19, 319-324.

Levenson, J. M., Roth, T. L., Lubin, F. D., Miller, C. A., Huang, I.-C., Desai, P, et al. (2006). Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. The Journal of Biological Chemistry, 281, 15763-15773.

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

Li, Z., Gu, T.-P, Weber, A. R., Shen, J.-Z., Li, B.-Z., Xie, Z.-G., et al. (2015). Gadd45a promotes DNA demethylation through TDG. Nucleic Acids Research, 43, 3986-3997.

Lister, R., Mukamel, E. A., Nery, J. R., Urich, M., Puddifoot, C. A., Johnson, N. D., et al. (2013). Global epigenomic reconfiguration during mammalian brain development. Science, 341, 1237905.

Lubin, F. D., Roth, T. L., & Sweatt, J. D. (2008). Epigenetic regulation of bdnf gene transcription in the consolidation of fear memory. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 28, 10576-10586.

Lyko, F., Ramsahoye, B. H., & Jaenisch, R. (2000). DNA methylation in Drosophila melanogaster. Nature, 408, 538-540.

Ma, D. K., Jang, M.-H., Guo, J. U., Kitabatake, Y, Chang, M., Pow-anpongku, N., et al. (2009). Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science, 323, 1074-1077.

Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu,Y., et al. (2003). DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science, 302, 890-893.

Mazin, A. L., & Vanyushin, B. F. (1988). Loss of CpG dinucleotides from DNA. 5. Traces of “fossil” methylation in Drosophila genome. Molecular Biology (Moscow), 22, 1399-1404.

McGowan, P. O., Sasaki, A., D’Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342-348.

Miller, C. A., Gavin, C. F, White, J. A., Parrish, R. R., Honasoge, A.,Yancey, C. R., et al. (2010). Cortical DNA methylation maintains remote memory. Nature Neuroscience, 13, 664-666.

Miller, C. A., & Sweatt, J. D. (2007). Covalent modification of DNA regulates memory formation. Neuron, 53, 857-869.

Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 28, 9055-9065.

Murgatroyd, C., Patchev, A. V., Wu, Y, Micale, V., Bockmuhl, Y., Fischer, D., et al. (2009). Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience, 12, 1559-1566.

Ng, H.-H., Zhang, Y, Hendrich, B., Johnson, C. A., Turner, B. M., Erdjument-Bromage, H., et al. (1999). MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genetics, 23, 58-61.

Okano, M., Bell, D. W., Haber, D. A., & Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 99, 247-257.

Okano, M., Xie, S., & Li, E. (1998a). Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Research, 26, 2536-2540.

Okano, M., Xie, S., & Li, E. (1998b). Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genetics, 19, 219-220.

Paroush, Z., Keshet, I., Yisraeli, J., & Cedar, H. (1990). Dynamics of demethylation and activation of the a-actin gene in myoblasts. Cell, 63, 1229-1237.

Pierfelice, T., Alberi, L., & Gaiano, N. (2011). Notch in the vertebrate nervous system: an old dog with new tricks. Neuron, 69, 840-855.

Rai, K., Huggins, I. J., James, S. R., Karpf, A. R., Jones, D. A., & Cairn, B. R. (2008). DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and Gadd45. Cell, 135, 1201-1212.

Ramsahoye, B. H., Biniszkiewicz, D., Lyko, F., Clark, V., Bird, A. P, & Jaenisch, R. (2000). Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proceedings of the National Academy of Sciences of the United States of America, 97, 5237-5242.

Razin, A., & Riggs, A. D. (1980). DNA methylation and gene function. Science, 210, 604-610.

Razin, A., Szyf, M., Kafri, T., Roll, M., Giloh, H., Scarpa, S., et al. (1986). Replacement of 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation. Proceedings of the National Academy of Sciences of the United States of America, 83, 2827-2831.

Riggs, A. D. (1975). X inactivation, differentiation, and DNA methylation. Cytogenetics and Cell Genetics, 14, 9-25.

Romanov, G. A., & Vanyushin, B. F. (1981). Methylation of reiterated sequences in mammalian DNAs: effects of the tissue type, age, malignancy and hormonal induction. Biochimica et Biophysica Acta, 653, 204-218.

Salvador, J. M., Brown-Clay, J. D., & Fornace, A. J., Jr. (2013). Gadd45 in stress signaling, cell cycle control, and apoptosis. In D. A. Liebermann, & B. Hoffman (Eds.), Gadd45 stress sensor genes (pp. 1-19). NewYork: Springer Science+Business Media.

Stein, R., Gruenbaum, Y, Pollack, Y, Razin, A., & Cedar, H. (1982). Clonal inheritance of the pattern of DNA methylation in mouse cells. Proceedings of the National Academy of Sciences of the United States of America, 79, 61-65.

Sultan, F. A., Wang, J., Tront, J., Liebermann, D. A., & Sweatt, J. D. (2012). Genetic deletion of gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 32, 17059—17066.

Sutter, D., & Doerfler, W (1980). Methylation of integrated adenovirus type 12 DNA sequences in transformed cells is inversely correlated with viral gene expression. Proceedings of the National Academy of Sciences of the United States of America, 77, 253—256.

Tahiliani, M., Koh, K. P., Shen, Y, Pastor, W. A., Bandukwala, H., Brudno, Y, et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324, 930-935.

Toth, M., Mueller, U., & Doerfler, W. (1990). Establishment of de novo DNA methylation patterns: transcription factor binding and deoxycytidine methylation at CpG and non-CpG sequences in an integrated adenovirus promoter. Journal of Molecular Biology, 214, 673-683.

Vanyushin, B. F., Alexandrushkina, N. I., & Kirnos, M. D. (1988). N6-methyladenine in mitochondrial DNA of higher plants. FEBS Letters, 233, 397-399.

Vanyushin, B. F, & Belozersky, A. N. (1959). The nucleotide composition of the deoxyribonucleic acids of higher plants. Doklady Akademii Nauk SSSR, 129, 944—946.

Vanyushin, B. F., Belyaeva, N. N., Kokurina, N. A., Stelmashchyuk, V. Y, & Tikhonenko, A. S. (1970). Characteristics of an uracil containing DNA of phage AR 9 Bacillus subtilis. Molecular Biology (Moscow), 4, 724-729.

Vanyushin, B. F., & Kirnos, M. D. (1974). The nucleotide composition and pyrimidine clusters in DNA from beef heart mitochondria. FEBS Letters, 39, 195-199.

Vanyushin, B. F., Mazin, A. L., Vasilyev, V K., & Belozersky, A. N. (1973). The content of 5-methylcytosine in animal DNA: the species and tissue specificity. Biochimica et Biophysica Acta, 299, 397-403.

Vanyushin, B. F., Nemirovsky, L. E., Klimenko, V V., Vasiliev, V K., & Belozersky, A. N. (1973). The 5-methyl- cytosine in DNA of rats: tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia (Basel), 19, 138-152.

Vanyushin, B. F., Tkacheva, S. G., & Belozersky, A. N. (1970). Rare bases in animal DNA. Nature, 225, 948949.

Vanyushin, B. F, Tushmalova, N. A., & Guskova, L. V (1974). Brain DNA methylation as an index of genome participation in mechanisms of memory formation. Doklady Akademii Nauk SSSR, 219, 742-744.

Vanyushin, B. F., Tushmalova, N. A., Guskova, L.V., Demidkina, N. P, & Nikandrova, L. R. (1977). The DNA methylation levels change in the rat brain on conditioned reflex elaboration. Molecular Biology (Moscow), 11, 181-187.

Varley, K. E., Gertz, J., Bowling, K. M., Parker, S. L., Reddy, T. E., Pauli-Behn, F, et al. (2013). Dynamic DNA methylation across diverse human cell lines and tissues. Genome Research, 23, 555-567.

Waalwijk, C., & Flavell, R. A. (1978). DNA methylation at a CCGG sequence in the large intron of the rabbit p-globin gene: tissue-specific variations. Nucleic Acids Research, 5, 4631-4642.

Weaver, I. C. G., Cervoni, N., Champagne, F A., D’Alessio, A. C., Sharma, S., Seck, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847-854.

Weaver, I. C. G., Meaney, M. J., & Szyf, M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proceedings of the National Academy of Sciences of the United States of America, 103, 3480-3485.

Wigler, M., Levy, D., & Perucho, M. (1981). The somatic replication of DNA methylation. Cell, 24, 33-40.

Wilson, V. L., Smith, R. A., Mag, S., & Cutler, R. G. (1987). Genomic 5-methyldeoxycytidine decreases with age. The Journal of Biological Chemistry, 262, 9948-9951.

Woodcock, D. M., Crowther, P. J., & Diver, W. P. (1987). The majority of methylated deoxycytidines in human DNA are not in the CpG dinucleotide. Biochemical and Biophysical Research Communications, 145, 888-894.

Wu, H., Coskun, V., Tao, J., Xie, W, Ge, W, Yoshikawa, K., et al. (2010). Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science, 329, 444-448.

Wyatt, G. R. (1950). Occurrence of 5-methylcytosine in nucleic acids. Nature, 166, 237-238.

Xie, W, Barr, C. L., Kim, A., Yue, F., Lee, A. Y, Eubanks, J., et al. (2012). Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell, 148, 816—831.

Yen, R.-W. C., Vertino, P. M., Nelkin, B. D., Yu, J. J., El-Deiry, W., Cumaraswamy, A., et al. (1992). Isolation and characterization of the cDNA encoding human DNA methyltransferase. Nucleic Acids Research, 20, 2287-2291.

Zhang, G., Huang, H., Liu, D., Cheng, Y, Liu, X., Zhang, W., et al. (2015). N6-Methyladenine DNA modification in Drosophila. Cell, 161, 893-906.

Ziller, M. J., Muller, F., Liao, J., Zhang, Y, Gu, H., Bock, C., et al. (2011). Genomic distribution and intersample variation of non-CpG methylation across human cell types. PLoS Genetics, 7, e1002389.

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