БИОХИМИЯ, 2020, том 85, вып. 9, с. 1139–1158

УДК 612.822;577.1

Эпигенетическая регуляция как основа долговременных изменений в нервной системе: в поисках механизмов специфичности*

Обзор

© 2020 А.А. Бородинова **, П.М. Балабан

Институт высшей нервной деятельности и нейрофизиологии РАН, 117485 Москва, Россия; электронная почта: borodinova.msu@mail.ru

Поступила в редакцию 01.06.2020
После доработки 16.07.2020
Принята к публикации 29.07.2020

DOI: 10.31857/S0320972520090018

КЛЮЧЕВЫЕ СЛОВА: память, обучение, эпигенетика, экспрессия генов, гистондеацетилаза, метилирование ДНК, оксид азота.

Аннотация

Долговременные адаптивные изменения функционирования нервной системы (пластичность, память) прямо связаны с изменением уровней экспрессии многих генов, но не отражаются в структуре ДНК, то есть являются проявлением эпигенетической регуляции. Суммируя известные данные о роли эпигенетических процессов и путей регуляции и хранения изменений в нервной системе, можно выделить несколько ключевых моментов. (1) Разнообразные факторы, управляющие структурной перестройкой хроматина и ДНК-метилтрансферазы в составе сложных мультибелковых репрессорных комплексов, координированно и кооперативно функционируют в качестве «молекулярных тормозов» («molecular brake pad»), избирательно сохраняя низкий уровень экспрессии только некоторых генов в условиях покоя. (2) В ответ на значимые физиологические стимулы в активированных нейронах запускается каскад биохимических событий, сопряженных с транспортом различных активаторных молекул (протеинкиназы, NO-содержащие комплексы) в ядро. (3) Стимул-специфичное нитрозилирование и фосфорилирование отдельных эпигенетических факторов сопряжено со снижением их ферментативной активности или изменением внутриклеточной локализации, что выражается во временной дестабилизации репрессорных комплексов. (4) Снятие «молекулярных тормозов» открывает «критическое окно» для глобальных и локальных эпигенетических перестроек, запуска специфических транскрипционных программ и модуляции эффективности синаптических связей. Можно считать, что обратимые посттрансляционные модификации гистонов служат основой для пластических изменений в функциональных сетях нейронов. С другой стороны, метилирование ДНК и метил-зависимые способы трехмерной организации хроматина могут служить стабильной молекулярной основой для долговременного хранения пластических изменений и памяти.

Сноски

* Статья на английском языке опубликована в режиме Open Access (открытого доступа) на сайте издательства Springer (https://link.springer.com/journal/10541), том 85, вып. 9, 2020.

** Адресат для корреспонденции.

Финансирование

Исследование выполнено при финансовой поддержке Российского фонда фундаментальных исследований (грант № 19-115-50290).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит исследований с участием людей или использованием животных в качестве объектов.

Список литературы

1. Alberini, C. M., and Kandel, E. R. (2014) The regulation of transcription in memory consolidation, Cold Spring Harb. Perspect. Biol., 7, a021741, doi: 10.1101/cshperspect.a021741.

2. Kyrke-Smith, M., and Williams, J. M. (2018) Bridging synaptic and epigenetic maintenance mechanisms of the engram, Front. Mol. Neurosci., 11, 369.

3. Halder, R., Hennion, M., Vidal, R. O., Shomroni, O., Rahman, R. U., Rajput, A., Centeno, T. P., van Bebber, F., Capece, V., Garcia Vizcaino, J. C., Schuetz, A. L., Burkhardt, S., Benito, E., Navarro Sala, M., Javan, S. B., Haass, C., Schmid, B., Fischer, A., and Bonn, S. (2016) DNA methylation changes in plasticity genes accompany the formation and maintenance of memory, Nat. Neurosci., 19, 102-110.

4. Jarome, T. J., and Lubin, F. D. (2014) Epigenetic mechanisms of memory formation and reconsolidation, Neurobiol. Learn. Mem., 115, 116-127.

5. Penney, J., and Tsai, L. H. (2014) Histone deacetylases in memory and cognition, Sci. Signal., 7, re12, doi: 10.1126/scisignal.aaa0069.

6. Kim, S., and Kaang, B. K. (2017) Epigenetic regulation and chromatin remodeling in learning and memory, Exp. Mol. Med., 49, e281.

7. Montarolo, P. G., Goelet, P., Castellucci, V. F., Morgan, J., Kandel, E. R., and Schacher, S. (1986) A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia, Science, 234, 1249-1254.

8. Guan, Z., Giustetto, M., Lomvardas, S., Kim, J. H., Miniaci, M. C., Schwartz, J. H., Thanos, D., and Kandel, E. R. (2002) Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure, Cell, 111, 483-493.

9. Ganai, S. A., Ramadoss, M., and Mahadevan, V. (2016) Histone deacetylase (HDAC) inhibitors – emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration, Curr. Neuropharmacol., 14, 55-71.

10. Latcheva, N. K., Viveiros, J. M., Waddell, E. A., Nguyen, P. T. T., Liebl, F. L. W., and Marenda, D. R. (2018) Epigenetic crosstalk: pharmacological inhibition of HDACs can rescue defective synaptic morphology and neurotransmission phenotypes associated with loss of the chromatin reader Kismet, Mol. Cell. Neurosci., 87, 77-85.

11. Торопова K. A., Анохин K. В., Тиунова A. A. (2014) Блокада деацетилирования гистонов в мозге модулирует экспрессию транскрипционных факторов c-Fos и ZENK и потенциирует образование долговременной памятиу новорожденных цыплят, Журнал Высшей Нервной Деятельности им. И.П. Павлова, 64, 551-561.

12. Zuzina, A., Vinarskaya, A., and Balaban, P. (2020) Histone deacetylase inhibitors rescue the impaired memory in terrestrial snails, J. Compar. Physiol. A, 206, 639-649, doi: 10.1007/s00359-020-01422-w.

13. Guan, J. S., Haggarty, S. J., Giacometti, E., Dannenberg, J. H., Joseph, N., Gao, J., Nieland, T. J., Zhou, Y., Wang, X., Mazitschek, R., Bradner, J. E., DePinho, R. A., Jaenisch, R., and Tsai, L. H. (2009) HDAC2 negatively regulates memory formation and synaptic plasticity, Nature, 459, 55-60.

14. Morris, M. J., Mahgoub, M., Na, E. S, Pranav, H., and Monteggia, L. M. (2013) Loss of histone deacetylase 2 improves working memory and accelerates extinction learning, J. Neurosci., 33, 6401-6411.

15. Ванюшин Б. Ф., Тушмалова Н. А., Гуськова Л. В. (1974) Метилирование ДНК мозга как показатель участия генома в механизмах индивидуально приобретенной памяти, Доклады АН СССР, 219, 742-744.

16. Гуськова Л. В., Бурцева Н. Н., Тушмалова Н. А., Ванюшин Б. Ф. (1977) Уровень метилирования ДНК ядер нейронов и глии коры больших полушарий мозга крыс и его изменения при выработке условного рефлекса, Доклады АН СССР, 233, 993-996.

17. Holliday, R. (1999) Is there an epigenetic component in long-term memory? J. Theor. Biol., 200, 339-341.

18. Day, J. J., and Sweatt, J. D. (2010) DNA methylation and memory formation, Nat. Neurosci., 13, 1319-1323.

19. Pearce, K., Cai, D., Roberts, A. C., and Glanzman, D. L. (2017) Role of protein synthesis and DNA methylation in the consolidation and maintenance of long-term memory in Aplysia, Elife, 6, e18299.

20. Duke, C. G., Kennedy, A. J., Gavin, C. F., Day, J. J., and Sweatt, J. D. (2017) Experience-dependent epigenomic reorganization in the hippocampus, Learn. Mem., 24, 278-288.

21. Miller, C. A., Gavin, C. F., White, J. A., Parrish, R. R., Honasoge, A., Yancey, C. R., Rivera, I. M., Rubio, M. D., Rumbaugh, G., and Sweatt, J. D. (2010) Cortical DNA methylation maintains remote memory, Nat. Neurosci., 13, 664-666.

22. Gupta, S., Kim, S. Y., Artis, S., Molfese, D. L., Schumacher, A., Sweatt, J. D., Paylor, R. E., and Lubin, F. D. (2010) Histone methylation regulates memory formation, J. Neurosci., 30, 3589-3599.

23. Lesburguères, E., Gobbo, O. L., Alaux-Cantin, S., Hambucken, A., Trifilieff, P., and Bontempi, B. (2011) Early tagging of cortical networks is required for the formation of enduring associative memory, Science, 331, 924-928.

24. Gulmez Karaca, K., Kupke, J., Brito, D. V. C., Zeuch, B., Thome, C., Weichenhan, D., Lutsik, P., Plass, C., and Oliveira, A. M. M. (2020) Neuronal ensemble-specific DNA methylation strengthens engram stability, Nat. Commun., 11, 639.

25. Gräff, J., Woldemichael, B. T., Berchtold, D., Dewarrat, G., and Mansuy, I. M. (2012) Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation, Nat. Commun., 3, 991.

26. Gupta-Agarwal, S., Franklin, A. V., Deramus, T., Wheelock, M., Davis, R. L., McMahon, L. L., andLubin, F. D. (2012) G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation, J. Neurosci., 32, 5440-5453.

27. Sui, L., Wang, Y., Ju, L. H., and Chen, M. (2012) Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex, Neurobiol. Learn. Mem., 97, 425-440.

28. Webb, W. M., Sanchez, R. G., Perez, G., Butler, A. A., Hauser, R. M., Rich, M. C., O’Bierne, A. L., Jarome, T. J., and Lubin, F. D. (2017) Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory, Neurobiol. Learn. Mem., 142, 66-78.

29. Kitamura, T., Ogawa, S. K., Roy, D. S., Okuyama, T., Morrissey, M. D., Smith, L. M., Redondo, R. L., and Tonegawa, S. (2017) Engrams and circuits crucial for systems consolidation of a memory, Science, 356, 73-78.

30. Бородинова A. A., Саложин С. В. (2016) Различия биологических функций BDNF и proBDNF в центральной нервной системе, Журнал Высшей Нервной Деятельности им. И.П. Павлова, 66, 3-23.

31. Bosch, C., Muhaisen, A., Pujadas, L., Soriano, E., and Martínez, A. (2016) Reelin exerts structural, biochemical and transcriptional regulation over presynaptic and postsynaptic elements in the adult hippocampus, Front. Cell. Neurosci., 10, 138.

32. Valiati, F. E., Vasconcelos, M., Lichtenfels, M., Petry, F. S., de Almeida, R. M. M., Schwartsmann, G., Schröder, N., de Farias, C. B., and Roesler, R. (2017) Administration of a histone deacetylase inhibitor into the basolateral amygdala enhances memory consolidation, delays extinction, and increases hippocampal BDNF levels, Front. Pharmacol., 8, 415.

33. Hermey, G., Mahlke, C., Gutzmann, J. J., Schreiber, J., Blüthgen, N., and Kuhl, D. (2013) Genome-wide profiling of the activity-dependent hippocampal transcriptome, PLoS One., 8, e76903.

34. Benito, E., and Barco, A. (2015) The neuronal activity-driven transcriptome, Mol. Neurobiol., 5, 1071-1088.

35. Fowler, T., Sen, R., and Roy, A. L. (2011) Regulation of primary response genes, Mol. Cell, 44, 348-360.

36. Herschman, H, R. (1991) Primary response genes induced by growth factors and tumor promoters, Annu. Rev. Biochem., 60, 281-319.

37. Tyssowski, K. M., DeStefino, N. R., Cho, J. H., Dunn, C. J., Poston, R. G., Carty, C. E., Jones, R. D., Chang, S. M., Romeo, P., Wurzelmann, M. K., Ward, J. M., Andermann, M. L., Saha, R. N., Dudek, S. M., and Gray, J. M. (2018) Different neuronal activity patterns induce different gene expression programs, Neuron, 98, 530-546.e11.

38. Tyssowski, K. M., Letai, K. C., Rendall, S. D., Tan, C., Nizhnik, A., Kaeser, P. S., and Gray, J. M. (2019) Firing rate homeostasis can occur in the absence of neuronal activity-regulated transcription, J. Neurosci., 39, 9885-9899.

39. Shepherd, J. D., and Bear, M. F. (2011) New views of Arc, a master regulator of synaptic plasticity, Nat. Neurosci., 14, 279-284.

40. Sacktor, T. C. (2011) How does PKMζ maintain long-term memory? Nat. Rev. Neurosci., 12, 9-15.

41. McQuown, S. C., and Wood, M. A. (2011) HDAC3 and the molecular brake pad hypothesis, Neurobiol. Learn. Mem., 96, 27-34.

42. Kelly, R. D., and Cowley, S. M. (2013) The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts, Biochem. Soc. Trans., 4, 741-749.

43. Fuks, F., Burgers, W. A., Godin, N., Kasai, M., and Kouzarides, T. (2001) Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription, EMBO J., 20, 2536-2544.

44. Fischle, W., Dequiedt, F., Hendzel, M. J., Guenther, M. G., Lazar, M. A., Voelter, W., and Verdin, E. (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR, Mol. Cell, 9, 45-57.

45. Galasinski, S. C., Resing, K. A., Goodrich, J. A., and Ahn, N. G. (2002) Phosphatase inhibition leads to histone deacetylases 1 and 2 phosphorylation and disruption of corepressor interactions, J. Biol. Chem., 277, 19618-19626.

46. Vaute, O., Nicolas, E., Vandel, L., and Trouche, D. (2002) Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases, Nucleic Acids Res., 30, 475-481.

47. Bai, S., Ghoshal, K., Datta, J., Majumder, S., Yoon, S. O., and Jacob, S. T. (2005) DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2, Mol. Cell. Biol., 25, 751-766.

48. Koshibu, K., Graff, J., Beullens, M., Heitz, F. D., Berchtold, D., Russig, H., Farinelli, M., Bollen, M., and Mansuy, I. M. (2009) Protein phosphatase 1 regulates the histone code for long-term memory, J. Neurosci., 29, 13079-13089.

49. Kundakovic, M., Chen, Y., Guidotti, A., and Grayson, D. R. (2009) The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes, Mol. Pharmacol., 75, 342-354.

50. Toffolo, E., Rusconi, F., Paganini, L., Tortorici, M., Pilotto, S., Heise, C., Verpelli, C., Tedeschi, G., Maffioli, E., Sala, C., Mattevi, A., and Battaglioli, E. (2014) Phosphorylation of neuronal lysine-specific demethylase 1LSD1/KDM1A impairs transcriptional repression by regulating interaction with CoREST and histone deacetylases HDAC1/2, J. Neurochem., 128, 603-616.

51. Mathias, R. A., Guise, A. J., and Cristea, I. M. (2015) Post-translational modifications regulate class IIa histone deacetylase (HDAC) function in health and disease, Mol. Cell. Proteomics., 14, 456-470.

52. Bayraktar, G., and Kreutz, M. R. (2018) Neuronal DNA methyltransferases: epigenetic mediators between synaptic activity and gene expression? Neuroscientist, 24, 171-185.

53. Riccio, A., Alvania, R. S., Lonze, B. E., Ramanan, N., Kim, T., Huang, Y., Dawson, T. M., Snyder, S. H., and Ginty, D. D. (2006) A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons, Mol. Cell, 21, 283-294.

54. Nott, A., Watson, P. M., Robinson, J. D., Crepaldi, L., and Riccio A. (2008) S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons, Nature, 455, 411-415.

55. Louis Sam Titus, A. S. C., Sharma, D., Kim, M. S., and D’Mello, S. R. (2019) The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression, BMC Neurosci., 20, 65.

56. Guenther, M. G., Barak, O., and Lazar, M. A. (2001) The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3, Mol. Cell. Biol., 21, 6091-6101.

57. Broide, R. S., Redwine, J. M., Aftahi, N., Young, W., Bloom, F. E., and Winrow, C. J. J. (2007) Distribution of histone deacetylases 1-11 in the rat brain, Mol. Neurosci., 31, 47-58.

58. Sando, R. 3rd, Gounko, N., Pieraut, S., Liao, L., Yates, J. 3rd, and Maximov, A. (2012) HDAC4 governs a transcriptional program essential for synaptic plasticity and memory, Cell, 151, 821-834.

59. Zhu, Y., Huang, M., Bushong, E., Phan, S., Uytiepo, M., Beutter, E., Boemer, D., Tsui, K., Ellisman, M., and Maximov, A. (2019) Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription, Nat. Commun., 10, 3469.

60. Chawla, S., Vanhoutte, P., Arnold, F. J., Huang, C. L., and Bading, H. (2003) Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5, J. Neurochem., 85, 151-159.

61. Schlumm, F., Mauceri, D., Freitag, H. E., and Bading, H. (2013) Nuclear calcium signaling regulates nuclear export of a subset of class IIa histone deacetylases following synaptic activity, J. Biol. Chem., 288, 8074-8084.

62. Josselyn, S. A., and Frankland, P. W. (2018) Memory allocation: mechanisms and function, Annu. Rev. Neurosci., 41, 389-413.

63. Zhang, C. L., McKinsey, T. A., and Olson, E. N. (2002) Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation, Mol. Cell. Biol., 22, 7302-7312.

64. Paroni, G., Cernotta, N., Dello Russo, C., Gallinari, P., Pallaoro, M., Foti, C., Talamo, F., Orsatti, L., Steinkühler, C., and Brancolini, C. (2008) PP2A regulates HDAC4 nuclear import, Mol. Biol. Cell, 19, 655-667.

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

66. Du, J., Johnson, L. M., Jacobsen, S. E., and Patel, D. J. (2015) DNA methylation pathways and their crosstalk with histone methylation, Nat. Rev. Mol. Cell Biol., 16, 519-532.

67. Denis, H., Ndlovu, M. N., and Fuks, F. (2011) Regulation of mammalian DNA methyltransferases: a route to new mechanisms, EMBO Rep., 12, 647-656.

68. Fuks, F., Hurd, P. J., Deplus, R., and Kouzarides, T. (2003) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase, Nucleic Acids Res., 31, 2305-2312.

69. Vasudevan, D., Bovee, R. C., and Thomas, D. D. (2016) Nitric oxide, the new architect of epigenetic landscapes, Nitric Oxide, 59, 54-62.

70. Balaban, P. M., Roshchin, M., Timoshenko, A. K., Gainutdinov, K. L., Bogodvid, T. K., Muranova, L. N., Zuzina, A. B., and Korshunova, T. A. (2014) Nitric oxide is necessary for labilization of a consolidated context memory during reconsolidation in terrestrial snails, Eur. J. Neurosci., 40, 2963-2970.

71. Gräff, J., Joseph, N. F., Horn, M. E., Samiei, A., Meng, J., Seo, J., Rei, D., Bero, A. W., Phan, T. X., Wagner, F., Holson, E., Xu, J., Sun, J., Neve, R. L., Mach, R. H., Haggarty, S. J., and Tsai, L. H. (2014) Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories, Cell, 156, 261-276.

72. Smith, J. G., Aldous, S. G., Andreassi, C., Cuda, G., Gaspari, M., and Riccio, A. (2018) Proteomic analysis of S-nitrosylated nuclear proteins in rat cortical neurons, Sci. Signal., 11, aar3396, doi: 10.1126/scisignal.aar3396.

73. Kornberg, M. D., Sen, N., Hara, M. R., Juluri, K. R., Nguyen, J. V., Snowman, A. M., Law, L., Hester, L. D., and Snyder, S. H. (2010) GAPDH mediates nitrosylation of nuclear proteins, Nat. Cell Biol., 12, 1094-1100.

74. Nakamura, T., and Lipton, S. A. (2013) Emerging role of protein-protein transnitrosylation in cell signaling pathways, Antioxid. Redox Signal., 18, 239-249.

75. Sen, N., and Snyder, S. H. (2011) Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation, Proc. Natl. Acad. Sci. USA, 108, 20178-20183.

76. Pi, H. J., and Lisman, J. E. (2008) Coupled phosphatase and kinase switches produce the tristability required for long-term potentiation and long-term depression, J. Neurosci., 28, 13132-13138.

77. Koshibu, K., Graff, J., and Mansuy, I. M. (2011) Nuclear protein phosphatase-1: an epigenetic regulator of fear memory and amygdala long-term potentiation, Neuroscience, 173, 30-36.

78. Borodinova, A. A., Zuzina, A. B., and Balaban, P. M. (2017) Role of atypical protein kinases in maintenance of long-term memory and synaptic plasticity, Biochemistry (Mosccow), 82, 243-256.

79. Chwang, W. B., O’Riordan, K. J., Levenson, J. M., and Sweatt, J. D. (2006) ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning, Learn. Mem., 13, 322-328.

80. Ko, H. G., Kim, J. I., Sim, S. E., Kim, T., Yoo, J., Choi, S. L., Baek, S. H., Yu, W. J., Yoon, J. B., Sacktor, T. C., and Kaang, B. K. (2016) The role of nuclear PKMζ in memory maintenance, Neurobiol. Learn. Mem., 135, 50-56.

81. Canettieri, G., Morantte, I., Guzmán, E., Asahara, H., Herzig, S., Anderson, S. D., Yates, J. R. 3rd, and Montminy, M. (2003) Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex, Nat. Struct. Biol., 10, 175-181.

82. Zhang, X., Ozawa, Y., Lee, H., Wen, Y. D., Tan, T. H., Wadzinski, B. E., and Seto, E. (2005) Histone deacetyl-ase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4, Genes Dev., 19, 827-839.

83. Vecsey, C. G., Hawk, J. D., Lattal, K. M., Stein, J. M., Fabian, S. A., Attner, M. A., Cabrera, S. M., McDonough, C. B., Brindle, P. K., Abel, T., and Wood, M. A. (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation, J. Neurosci., 27, 6128-6140.

84. Graff, J., Koshibu, K., Jouvenceau, A., Dutar, P., and Mansuy, I. M. (2010) Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity, Learn. Mem., 17, 355-363.

85. Wooten, M. W., Zhou, G., Wooten, M. C., and Seibenhener, M. L. (1997) Transport of protein kinase C isoforms to the nucleus of PC12 cells by nerve growth factor: association of atypical zeta-PKC with the nuclear matrix, J. Neurosci. Res., 49, 393-403.

86. Sakagami, H., Kamata, A., Nishimura, H., Kasahara, J., Owada, Y., Takeuchi, Y., Watanabe, M., Fukunaga, K., and Kondo, H. (2005) Prominent expression and activity-dependent nuclear translocation of Ca2+/calmodulin-dependent protein kinase Idelta in hippocampal neurons, Eur. J. Neurosci., 22, 2697-2707.

87. Zhai, S., Ark, E. D., Parra-Bueno, P., and Yasuda, R. (2013) Long-distance integration of nuclear ERK signaling triggered by activation of a few dendritic spines, Science, 342, 1107-1111.

88. Melgarejo da Rosa, M., Yuanxiang, P., Brambilla, R., Kreutz, M. R., and Karpova, A. (2016) Synaptic GluN2B/CaMKII-α signaling induces synapto-nuclear transport of ERK and Jacob, Front. Mol. Neurosci., 9, 66.

89. Lavoie, G., Estève, P. O., Laulan, N. B., Pradhan, S., and St-Pierre, Y. (2011) PKC isoforms interact with and phosphorylate DNMT1, BMC Biol., 9, 31.

90. Wegner, M., Cao, Z., and Rosenfeld, M. G. (1992) Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta, 256, Science, 370-373.

91. He, L., Sabet, A., Djedjos, S., Miller, R., Sun, X., Hussain, M. A., Radovick, S., and Wondisford, F. E. (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein, Cell, 137, 635-646.

92. Wang, J., Weaver, I. C., Gauthier-Fisher, A., Wang, H., He, L., Yeomans, J., Wondisford, F., Kaplan, D. R., and Miller, F. D. (2010) CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein-Taybi syndrome brain, Dev. Cell, 18, 114-125.

93. Gouveia, A., Hsu, K., Niibori, Y., Seegobin, M., Cancino, G. I., He, L., Wondisford, F. E., Bennett, S., Lagace, D., Frankland, P. W., and Wang, J. (2016) The aPKC-CBP pathway regulates adult hippocampal neurogenesis in an age-dependent manner, Stem Cell Rep., 7, 719-734.

94. Kwok, R. P., Lundblad, J. R., Chrivia, J. C., Richards, J. P., Bächinger, H. P., Brennan, R. G., Roberts, S. G., Green, M. R., and Goodman, R. H. (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB, Nature, 370, 223-226.

95. Briand, L. A., Lee, B. G., Lelay, J., Kaestner, K. H., and Blendy, J. A. (2015) Serine 133 phosphorylation is not required for hippocampal CREB-mediated transcription and behavior, Learn. Mem., 22, 109-115.

96. Impey, S., Fong, A. L., Wang, Y., Cardinaux, J. R., Fass, D. M., Obrietan, K., Wayman, G. A., Storm, D. R., Soderling, T. R., and Goodman, R. H. (2002) Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV, Neuron., 34, 235-244.

97. Barrett, R. M., Malvaez, M., Kramar, E., Matheos, D. P., Arrizon, A., Cabrera, S. M., Lynch, G., Greene, R. W., and Wood, M. A. (2011) Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory, Neuropsychopharmacology, 36, 1545-1556.

98. Chen, S., Cai, D., Pearce, K., Sun, P. Y., Roberts, A. C., and Glanzman, D. L. (2014) Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in aplysia, Elife, 3, e03896.

99. Rao-Ruiz, P., Couey, J. J., Marcelo, I. M., Bouwkamp, C. G., Slump, D. E., Matos, M. R., van der Loo, R. J., Martins, G. J., van den Hout, M., van IJcken, W. F., Costa, R. M., van den Oever, M. C., and Kushner, S. A. (2019) Engram-specific transcriptome profiling of contextual memory consolidation, Nat. Commun., 10, 2232.

100. Bédécarrats, A., Chen, S., Pearce, K., Cai, D., and Glanzman, D. L. (2018) RNA from trained aplysia can induce an epigenetic engram for long-term sensitization in untrained aplysia, eNeuro, 5, doi: 10.1523/ENEURO.0038-18.2018.

101. Maurano, M. T., Wang, H., John, S., Shafer, A., Canfield, T., Lee, K., and Stamatoyannopoulos, J. A. (2015) Role of DNA methylation in modulating transcription factor occupancy, Cell Rep., 12, 1184-1195.

102. Phillips, J. E., and Corces, V. G. (2009) CTCF: master weaver of the genome, Cell, 137, 1194-1211.

103. Sams, D. S., Nardone, S., Getselter, D., Raz, D., Tal, M., Rayi, P. R., Kaphzan, H., Hakim, O., and Elliott, E. (2016) Neuronal CTCF is necessary for basal and experience-dependent gene regulation, memory formation, and genomic structure of BDNF and Arc, Cell Rep., 17, 2418-2430.

104. Kim, S., Yu, N. K., Shim, K. W., Kim, J. I., Kim, H., Han, D. H., Choi, J. E., Lee, S. W., Choi, D. I., Kim, M. W., Lee, D. S., Lee, K., Galjart, N., Lee, Y. S., Lee, J. H., and Kaang, B. K. (2018) Remote memory and cortical synaptic plasticity require neuronal CCCTC-binding factor (CTCF), J. Neurosci., 38, 5042-5052.

105. Savell, K. E., Gallus, N. V., Simon, R. C., Brown, J. A., Revanna, J. S., Osborn, M. K., Song, E. Y., O’Malley, J. J., Stackhouse, C. T., Norvil, A., Gowher, H., Sweatt, J. D., and Day, J. J. (2016) Extra-coding RNAs regulate neuronal DNA methylation dynamics, Nat. Commun., 7, 12091, doi: 10.1038/ncomms12091.

106. Балабан П. М., Бородинова А. А. (2019) Нейрогенетические технологии исследования механизмов хранения памяти, Рос. физиол. журн. им. И.М. Сеченова, 105, 1392-1405, doi: 10.1134/S0869813919110025.