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Review
.2022 Jan 19:15:25168657211072499.
doi: 10.1177/25168657211072499. eCollection 2022.

DNA Methylation and Establishing Memory

Affiliations
Review

DNA Methylation and Establishing Memory

Carol Bernstein. Epigenet Insights..

Abstract

A single event can cause a life-long memory. Memories physically reside in neurons, and changes in neuronal gene expression are considered to be central to memory. Early models proposed that specific DNA methylations of cytosines in neuronal DNA encode memories in a stable biochemical form. This review describes recent research that elucidates the molecular mechanisms used by the mammalian brain to form DNA methylcytosine encoded memories. For example, neuron activation initiates cytosine demethylation by stimulating DNA topoisomerase II beta (TOP2B) protein to make a temporary DNA double-strand break (repaired within about 2 hours) at a promoter of an immediate early gene,EGR1, allowing expression of this gene. The EGR1 proteins then recruit methylcytosine dioxygenase TET1 proteins to initiate demethylation at several hundred genes, facilitating expression of those genes. Initiation of demethylation of cytosine also occurs when OGG1 localizes at oxidized guanine in a methylated CpG site and recruits TET1 for initiation of demethylation at that site.DNMT3A2 is another immediate early gene upregulated by synaptic activity. DNMT3A2 protein catalyzes de novo DNA methylations. These several mechanisms convert external experiences into DNA methylations and initiated demethylations of neuronal DNA cytosines, causing changes in gene expression that are the basis of long-term memories.

Keywords: 8-oxoguanine glycosylase (OGG1); DNA demethylation; DNA methylation; DNA methyltransferase (DNMT); TET enzymes; cortex; early growth response gene 1 (EGR1); hippocampus; immediate early gene (IEG); long-term memory; memory; neuron; topoisomerase II beta.

© The Author(s) 2022.

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Conflict of interest statement

Declaration of Conflicting Interests: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Cytosine, when methylated, has a methyl group added on the 5 position as shown in red oval. The methyl group can be oxidized to form 5-hydroxymethylcytosine.
Figure 2.
Figure 2.
Panel A: Outer parts of the brain including cerebrum lobes. Panel B: Deep structures including brain regions involved in memory formation . Panel Ahttps://commons.wikimedia.org/wiki/File: Cerebrum_lobes.svg Vectorized by Jkwchui / CC BY-SA. Panel Bhttps://commons.wikimedia.org/wiki/File: Brain_regions_.involved_in_memory_formation.jpg In the public domain.
Figure 3.
Figure 3.
Enhancer promoter interactions. An active enhancer regulatory region is enabled to interact with the promoter region of its target gene by formation of a chromosome loop. This can initiate messenger RNA (mRNA) synthesis by RNA polymerase II (RNAP II) bound to the promoter at the transcription start site of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter and these proteins are joined together to form a dimer (red zigzags). Specific regulatory transcription factors bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as phosphorylation, shown by a small red star on a transcription factor on the enhancer) the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator (a complex consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.https://commons.wikimedia.org/wiki/File:Regulation_of_transcription_in_ma mmals.jpg Bemstein0275, CC BY-SA 4.0.
Figure 4.
Figure 4.
Drawing by Camillo Golgi of a hippocampus and dentate gyrus. Public domain.https://commons.wikimedia.org/wiki/File:Golgi_Hippocampus.jpg#file.
Figure 5.
Figure 5.
Paused RNA polymerase and limited, short-term TOP2B-induced DNA double-strand break. The 5′ ends of DNA are covalently joined to tyrosine within the TOP2B dimer. The NHEJ repair pathway components: DNA-PKcs, KU70/KU80 and DNA LIGASE IV are closely associated with the TOP2B dimer.https://commons.wikimedia.org/wiki/File:Regulatory_sequence in_a_promoter_at_a_transcriptio n_start site_with_a_paused RNA polymerase_and_a_TOP2B-induced_doublestrand_break.jpg Bernstein0275, CC BY-SA 4.0.
Figure 6.
Figure 6.
Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by a TET enzyme.https://commons.wikimedia.org/wiki/File:Conversion of 5methylcytosine_to 5-hydroxymetnylcytosine_by TET enzyme_plus_alphaketoglutarate & Fe(ll).jpg Bernstein0275, CC BY-SA 4.0.
Figure 7.
Figure 7.
A nucleosome showing 4 pairs of histones (H2A, H2B, H3, H4), each pair with the same color. The aminoterminal (N-terminal) tails of one of each pair of histones is shown, labeled with the positions of the lysine amino acids (“K” is the single letter code for lysine) that are subject to acetylation or methylation. The number at each lysine indicates its position counting from the amino end of the protein chain. Acetylations (Ac) and methylations (Me) are shown in some positions susceptible to these epigenetic alterations. The DNA, wound around the histone core, is indicated by the dark line.
Figure 8.
Figure 8.
Initiation of DNA demethylation at a CpG site. Image of a CpG site where cytosine is methylated to form 5methylcytosine (5mC) and the guanine is oxidized to form 8hydroxy-2′-deoxyguanosine (8-0HdG). The base excision repair enzyme OGGI targets and binds to 8-0HdG without immediate excision. OGGI recruits TETI and TETI oxidizes the 5mC adjacent to the 8-0HdG. This initiates demethylation of the 5mC.https://commons.wikimedia.org/wiki/File:lnitiation_of_DNA_demethylation_at_a_CPG_site.svg. Bernstein0275, CC BY-SA 4.0.
Figure 9.
Figure 9.
Dendritic spines (yellow) along a cultured hippocampal neuron. The bar is 5 µm. Part of an image fromhttps://commons.wikimedia.org/wiki/File:Cytoskeletal_organization_ of_dendritic_spines.jpg Hotulainen P. Hoogenraad CC., CC BY-SA 2.5.
Figure 10.
Figure 10.
Elements of a pathway from memorable event to long-term memory in the cortex.
See this image and copyright information in PMC

References

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