Editing Gene expression (section)

===Transcriptional regulation in learning and memory===
{{main|Epigenetics in learning and memory}}

[[File:Brain regions involved in memory formation.jpg|thumb|400 px|The identified areas of the human brain are involved in memory formation.]]

In a rat, contextual [[fear conditioning]] (CFC) is a painful learning experience. Just one episode of CFC can result in a life-long fearful memory.<ref name=KimJung>{{cite journal | vauthors = Kim JJ, Jung MW | title = Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review | journal = Neuroscience and Biobehavioral Reviews | volume = 30 | issue = 2 | pages = 188–202 | date = 2006 | pmid = 16120461 | pmc = 4342048 | doi = 10.1016/j.neubiorev.2005.06.005 }}</ref> After an episode of CFC, cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the [[hippocampus]] neuron DNA of a rat.<ref name=DukeSweatt>{{cite journal | vauthors = Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD | title = Experience-dependent epigenomic reorganization in the hippocampus | journal = Learning & Memory | volume = 24 | issue = 7 | pages = 278–288 | date = July 2017 | pmid = 28620075 | pmc = 5473107 | doi = 10.1101/lm.045112.117 }}</ref> The [[hippocampus]] is where new memories are initially stored. After CFC about 500 genes have increased transcription (often due to demethylation of CpG sites in a promoter region) and about 1,000 genes have decreased transcription (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain.<ref name=DukeSweatt />

Some specific mechanisms guiding new DNA methylations and new [[DNA demethylation]]s in the [[hippocampus]] during memory establishment have been established (see<ref name=Bernstein>{{cite journal | vauthors = Bernstein C | title = DNA Methylation and Establishing Memory | journal = Epigenetics Insights | volume = 15 | issue =  | pages = 25168657211072499 | date = 2022 | pmid = 35098021 | pmc = 8793415 | doi = 10.1177/25168657211072499 }}</ref> for summary).  One mechanism includes guiding the short isoform of the [[Tet methylcytosine dioxygenase 1|TET1]] [[DNA demethylation]] enzyme, TET1s, to about 600 locations on the genome.  The guidance is performed by association of TET1s with [[EGR1]] protein, a transcription factor important in memory formation.  Bringing TET1s to these locations initiates DNA demethylation at those sites, up-regulating associated genes. A second mechanism involves DNMT3A2, a splice-isoform of [[DNA methyltransferase]] DNMT3A, which adds methyl groups to cytosines in DNA.  This isoform is induced by synaptic activity, and its location of action appears to be determined by [[histone]] post-translational modifications (a [[histone code]]).  The resulting new [[messenger RNA]]s are then transported by [[messenger RNP]] particles (neuronal granules) to synapses of the neurons, where they can be translated into proteins affecting the activities of synapses.<ref name=Bernstein />

In particular, the [[brain-derived neurotrophic factor]] gene (''BDNF'') is known as a "learning gene".<ref name=Keifer>{{cite journal | vauthors = Keifer J | title = Primetime for Learning Genes | journal = Genes | volume = 8 | issue = 2 | page = 69 | date = February 2017 | pmid = 28208656 | pmc = 5333058 | doi = 10.3390/genes8020069 | doi-access = free }}</ref> After CFC there was upregulation of ''BDNF'' gene expression, related to decreased CpG methylation of certain internal promoters of the gene, and this was correlated with learning.<ref name=Keifer />