Editing Epigenetics (section)

====Memory====
{{main|Epigenetics in learning and memory}}

[[Encoding (memory)|Memory formation]] and maintenance are due to epigenetic alterations that cause the required dynamic changes in [[gene transcription]] that create and renew memory in neurons.<ref name="Bernstein"/>

An event can set off a chain of reactions that result in altered methylations of a large set of genes in neurons, which give a representation of the event, a memory.<ref name=Bernstein />

[[File:Brain regions in memory formation updated.jpg|thumb|including medial prefrontal cortex (mPFC)]]
Areas of the brain important in the formation of memories include the hippocampus, medial prefrontal cortex (mPFC), anterior cingulate cortex and amygdala, as shown in the diagram of the human brain in this section.<ref name="pmid28386011">{{cite journal |vauthors=Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, Redondo RL, Tonegawa S |title=Engrams and circuits crucial for systems consolidation of a memory |journal=Science |volume=356 |issue=6333 |pages=73–78 |date=April 2017 |pmid=28386011 |pmc=5493329 |doi=10.1126/science.aam6808 |bibcode=2017Sci...356...73K |url=}}</ref>

When a strong memory is created, as in a rat subjected to [[Fear conditioning|contextual fear conditioning]] (CFC), one of the earliest events to occur is that more than 100 DNA double-strand breaks are formed by [[topoisomerase|topoisomerase IIB]] in neurons of the hippocampus and the medial prefrontal cortex (mPFC).<ref name=Stott>{{cite journal |vauthors=Stott RT, Kritsky O, Tsai LH |title=Profiling DNA break sites and transcriptional changes in response to contextual fear learning |journal=PLOS ONE |volume=16 |issue=7 |pages=e0249691 |date=2021 |pmid=34197463 |pmc=8248687 |doi=10.1371/journal.pone.0249691 |bibcode=2021PLoSO..1649691S |url=|doi-access=free }}</ref> These double-strand breaks are at specific locations that allow activation of transcription of [[immediate early genes]] (IEGs) that are important in memory formation, allowing their expression in [[messenger RNA|mRNA]], with peak mRNA transcription at seven to ten minutes after CFC.<ref name=Stott /><ref name="pmid35776545">{{cite journal |vauthors=Lee BH, Shim JY, Moon HC, Kim DW, Kim J, Yook JS, Kim J, Park HY |title=Real-time visualization of mRNA synthesis during memory formation in live mice |journal=Proc Natl Acad Sci U S A |volume=119 |issue=27 |pages=e2117076119 |date=July 2022 |pmid=35776545 |pmc=9271212 |doi=10.1073/pnas.2117076119 |doi-access=free |bibcode=2022PNAS..11917076L |url=}}</ref>

Two important IEGs in memory formation are ''[[EGR1]]''<ref name="pmid10357227">{{cite journal |vauthors=Tischmeyer W, Grimm R |title=Activation of immediate early genes and memory formation |journal=Cell Mol Life Sci |volume=55 |issue=4 |pages=564–74 |date=April 1999 |pmid=10357227 |doi=10.1007/s000180050315 |s2cid=6923522 |url=|pmc=11146814 }}</ref> and [[DNA methyltransferase|the alternative promoter variant of ''DNMT3A'', ''DNMT3A2'']].<ref name="pmid22751036">{{cite journal |vauthors=Oliveira AM, Hemstedt TJ, Bading H |title=Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities |journal=Nat Neurosci |volume=15 |issue=8 |pages=1111–3 |date=July 2012 |pmid=22751036 |doi=10.1038/nn.3151 |s2cid=10590208 |url=}}</ref> EGR1 protein binds to DNA at its binding motifs, 5′-GCGTGGGCG-3′ or 5′-GCGGGGGCGG-3', and there are about 12,000 genome locations at which EGR1 protein can bind.<ref name=Sun>{{cite journal |vauthors=Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H |title=EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity |journal=Nat Commun |volume=10 |issue=1 |pages=3892 |date=August 2019 |pmid=31467272 |pmc=6715719 |doi=10.1038/s41467-019-11905-3 |bibcode=2019NatCo..10.3892S |url=}}</ref> EGR1 protein binds to DNA in gene [[Promoter (genetics)|promoter]] and [[Enhancer (genetics)|enhancer]] regions. EGR1 recruits the demethylating enzyme [[TET enzymes|TET1]] to an association, and brings TET1 to about 600 locations on the genome where TET1 can then demethylate and activate the associated genes.<ref name=Sun />

[[File:Cytosine and 5-methylcytosine.svg|thumb|Cytosine and 5-methylcytosine]]

The DNA methyltransferases DNMT3A1, DNMT3A2 and DNMT3B can all methylate cytosines (see image this section) at [[CpG site]]s in or near the promoters of genes. As shown by Manzo et al.,<ref name="pmid29074627">{{cite journal |vauthors=Manzo M, Wirz J, Ambrosi C, Villaseñor R, Roschitzki B, Baubec T |title=Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands |journal=EMBO J |volume=36 |issue=23 |pages=3421–3434 |date=December 2017 |pmid=29074627 |pmc=5709737 |doi=10.15252/embj.201797038 |url=}}</ref> these three DNA methyltransferases differ in their genomic binding locations and DNA methylation activity at different regulatory sites. Manzo et al. located 3,970 genome regions exclusively enriched for DNMT3A1, 3,838 regions for DNMT3A2 and 3,432 regions for DNMT3B. When DNMT3A2 is newly induced as an IEG (when neurons are activated), many new cytosine methylations occur, presumably in the target regions of DNMT3A2. Oliviera et al.<ref name="pmid22751036"/> found that the neuronal activity-inducible IEG levels of Dnmt3a2 in the hippocampus determined the ability to form long-term memories.

Rats form long-term associative memories after [[fear conditioning|contextual fear conditioning (CFC)]].<ref name="pmid25324744">{{cite journal |vauthors=Joels G, Lamprecht R |title=Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory |journal=Front Behav Neurosci |volume=8 |issue= |pages=324 |date=2014 |pmid=25324744 |pmc=4179742 |doi=10.3389/fnbeh.2014.00324 |url=|doi-access=free }}</ref> Duke et al.<ref name="pmid28620075"/> found that 24 hours after CFC in rats, in hippocampus neurons, 2,097 genes (9.17% of the genes in the rat genome) had altered methylation. When newly methylated cytosines are present in [[CpG site]]s in the promoter regions of genes, the genes are often repressed, and when newly demethylated cytosines are present the genes may be activated.<ref name="pmid22781841">{{cite journal |vauthors=Moore LD, Le T, Fan G |title=DNA methylation and its basic function |journal=Neuropsychopharmacology |volume=38 |issue=1 |pages=23–38 |date=January 2013 |pmid=22781841 |pmc=3521964 |doi=10.1038/npp.2012.112 |url=}}</ref> After CFC, there were 1,048 genes with reduced mRNA expression and 564 genes with upregulated mRNA expression. Similarly, when mice undergo CFC, one hour later in the hippocampus region of the mouse brain there are 675 demethylated genes and 613 hypermethylated genes.<ref name=Halder>{{cite journal |vauthors=Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Garcia Vizcaino JC, Schuetz AL, Burkhardt S, Benito E, Navarro Sala M, Javan SB, Haass C, Schmid B, Fischer A, Bonn S |title=DNA methylation changes in plasticity genes accompany the formation and maintenance of memory |journal=Nat Neurosci |volume=19 |issue=1 |pages=102–10 |date=January 2016 |pmid=26656643 |doi=10.1038/nn.4194 |s2cid=1173959 |url=}}</ref> However, memories do not remain in the hippocampus, but after four or five weeks the memories are stored in the anterior cingulate cortex.<ref name="pmid15131309">{{cite journal |vauthors=Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ |title=The involvement of the anterior cingulate cortex in remote contextual fear memory |journal=Science |volume=304 |issue=5672 |pages=881–3 |date=May 2004 |pmid=15131309 |doi=10.1126/science.1094804 |bibcode=2004Sci...304..881F |s2cid=15893863 |url=}}</ref> In the studies on mice after CFC, Halder et al.<ref name=Halder /> showed that four weeks after CFC there were at least 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the anterior cingulate cortex, while at the same time the altered methylations in the hippocampus were reversed.

The epigenetic alteration of methylation after a new memory is established creates a different pool of nuclear mRNAs. As reviewed by Bernstein,<ref name=Bernstein /> the epigenetically determined new mix of nuclear [[messenger RNA|mRNAs]] are often packaged into neuronal granules, or [[messenger RNP]], consisting of mRNA, [[ribosome|small and large ribosomal subunits]], translation initiation factors and RNA-binding proteins that regulate mRNA function. These neuronal granules are transported from the neuron nucleus and are directed, according to 3′ untranslated regions of the mRNA in the granules (their "zip codes"), to neuronal [[dendrite]]s. Roughly 2,500 mRNAs may be localized to the dendrites of hippocampal pyramidal neurons and perhaps 450 transcripts are in excitatory presynaptic nerve terminals (dendritic spines). The altered assortments of transcripts (dependent on epigenetic alterations in the neuron nucleus) have different sensitivities in response to signals, which is the basis of altered synaptic plasticity. Altered synaptic plasticity is often considered the neurochemical foundation of learning and memory.