Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms
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REVIEW
Epigenetic Regulation as a Basis for LongTerm Changes in the Nervous System: In Search of Specificity Mechanisms A. A. Borodinova1,a* and P. M. Balaban1 1
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia a email: [email protected] Received June 1, 2020 Revised July 16, 2020 Accepted July 29, 2020
Abstract—Adaptive longterm changes in the functioning of nervous system (plasticity, memory) are not written in the genome, but are directly associated with the changes in expression of many genes comprising epigenetic regulation. Summarizing the known data regarding the role of epigenetics in regulation of plasticity and memory, we would like to high light several key aspects. (i) Different chromatin remodeling complexes and DNA methyltransferases can be organized into highorder multiprotein repressor complexes that are cooperatively acting as the “molecular brake pads”, selectively restricting transcriptional activity of specific genes at rest. (ii) Relevant physiological stimuli induce a cascade of biochem ical events in the activated neurons resulting in translocation of different signaling molecules (protein kinases, NOcon taining complexes) to the nucleus. (iii) Stimulusspecific nitrosylation and phosphorylation of different epigenetic factors is linked to a decrease in their enzymatic activity or changes in intracellular localization that results in temporary destabiliza tion of the repressor complexes. (iv) Removing “molecular brakes” opens a “critical time window” for global and local epi genetic changes, triggering specific transcriptional programs and modulation of synaptic connections efficiency. It can be assumed that the reversible posttranslational histone modifications serve as the basis of plastic changes in the neural net work. On the other hand, DNA methylation and methylationdependent 3D chromatin organization can serve a stable molecular basis for longterm maintenance of plastic changes and memory. DOI: 10.1134/S0006297920090023 Keywords: memory, learning, epigenetics, gene expression, histone deacetylase, DNA methylation, nitric oxide
INTRODUCTION There is a vast number of studies regarding mecha nisms of memory, however, up to now there is no consen sus on molecular mechanisms of the formation and long term retention of the memory trace, as well as on effective approaches for changing the memory and correction of its pathologies. During the last years many data has been accumulated indicating that longterm changes in the nervous system, including memory, are associated with changes in the expression of certain gene groups [1, 2]. Understanding of how the specific control of the separate gene groups is realized at certain times in certain func tional neural networks during learning and what mecha nisms are behind the maintenance of these changes is very Abbreviations: DNMT, DNA methyltransferase; H3K(n), nth lysine of the third histone; HAT, histone acetyltransferase; HDAC, histone deacetylase; NO, nitric ox
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