Epigenetics of Memory

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Epigenetics of Memory

Gene regulation plays an integral role in cell survival and function. Recent studies have been providing evidence to supporting the involvement of epigenetic markers as the central mechanism to controlling gene expression.3,4,5 Our memory is a highly complex machinery that require precise control of gene expression and a certain level of plasticity that allows it to change and adapt to new experiences. However unlike cells in the rest of human body neurons do not divide and thus neurons do not have the luxury to adapt to external stimuli through mitosis but instead must do so through epigenetic markers.3 Though there are many ways a neuron can utilize epigenetic markers to regulate its gene expression the primary mechanisms include DNA methylation / demethylation and acetylation / deacetylation, these neuro-epigenetic markers work by transferring chemical groups onto DNA residues to achieve a local, gene specific regulation or it can act on histones for a more global, chromosome wide regulation.4 Epigenetic modifications are generally catalyzed by three main groups of enzymes called methyltransferase, acetyltransferase and kinases all of which are responsible for the modifications of genome via chemical groups that affects the dynamic of gene expression.1,4 Previous studies have shown that these enzymes are involved in memory formation and consolidation while deficiencies in the protein itself or its targets have been implicated in memory deficit and numerous psychotic disorders.3,4

1.0 DNA Modification

1.1 DNA Methylation

DNA methylation involves the addition of a methyl group onto the 5’ position of a cytosine pyrimidine ring catalysed by an enzyme called DNA methyltransferase (DNMT), The methylation of a cytosine residue creates an extremely stable carbon-carbon bond in which a large amount of energy is required to break this bond.3 The methylated cytosine residue (MeC) initiates the methylation of the complementary residue with the help of maintenance DNMTs, in the event of DNA damage or rare spontaneous demethylation where a methyl group is lost on one of the strand, the complementary residue serves as a template for the resynthesize of MeC, this mechanism grants DNA the ability to self-sustain its own methylations.2,3 Due to its high stability and ability to self sustain DNA methylation is often termed the Prima Donna of epigenetics.3 Studies in adult rats have shown that DNMT expression is increase in both associative learning and contextual fear learning while inhibition of DNMT activity leads to impaired learning, suggesting a clear relationship between levels of methylation and learning response.2,3,7 Activation of DNMT affects neurogenesis in the hippocampus, a quality thought to be important during memory formation, studies have shown that DNMT inhibitors decrease the expression of brain-derived neurotrophic factors (BDNF) which is a key element in neurogenesis. In addition, fear conditioning induces rapid methylation along with the silencing of protein phosphatase I (PPI) that has been shown to be involved in memory suppression.2,3,4,7

Demethylation is essential to brain plasticity. Given the highly stable carbon-carbon bond in MeC, demethylation is highly unfavourable so instead a theory was proposed that MeC would undergo a deamination reaction which would result in the conversion into thymine followed by a base excision repair catalysed by TDG glycosylase, a member of the DNA repair machinery that would replace thymine with unmethylated cytosine.2,3 However it is still unclear what type of impact this process would have on the complementary strand.

2.0 Histone modification

Unlike DNA modification, histone modifications take place on a nucleosome which is composed of 4 subunit called histones (H2A, H2B, H3, H4).6 The organization of these nucleosomes directly influence gene expression as it allows a certain part of the genome to be in a ‘closed’ or ‘open’ conformation and will control the accessibility of transcription factors. The N-terminal tail of each histone subunit is where most epigenetic modifications take place and these modifications will be recognized by chromatin-associated enzymatic complex which will reorganize the chromosome structure based on the modifications that are presented on the histone tails.5,6

2.1 Methylation

Histone methylation produces a more global control on gene expression as it affects the structure of chromosome. Histone methylation is catalysed by histone methyltransferase and its effect depends on target amino acid residue (lysine being the most common) and the number of methyl groups added.4 Previous studies have shown that dimethylation of lysine at the ninth position of histone H3 (H3K9) correlates with transcriptional inhibition while trimethylation of H3k4 promotes transcription, both of which have been implicated to upregulate following contextual fear conditioning in recent studies.4,5 Furthermore, histone methylation is able to serve as a signal for recruiting DNMTs onto specific segment of a gene, increasing its specificity for binding and thus gives DNMT more precise control over gene expression.3

2.2 Acetylation

Acetylation of the genome involves the addition of an acetyl group onto the lysine residue of a histone by enzymes called histone acetyltransferase (HAT), this modification often leads to the recruitment of other regulatory proteins that possess a recognition domain which are capable of binding to the modified lysine residue in order to drive transcription by changing chromosome structure to allow easier access by transcription factors.6 Aside from the ability to transfer acetyl groups onto histone, certain HATs also posses a bromodomain which is also capable of recognizing acetylated lysine residue, giving it the potential for self regulation.4,6 Earlier studies have also suggested that DNA methylation in CA1 area of the hippocampus promotes histone acetylation and vice versa, studies shown that inhibitors of histone deacetylase (HDAC) is able to rescue to memory deficit effects caused by DNMT inhibitors, however HDAC inhibitors does not cause a global acetylation of the genome but instead it targets a very specific group of memory promoting genes such as Nr4a1 which leads to enhanced memory formation.8

2.3 Phosphorylation

Phosphorylation of a histone requires the transfer of a phosphate group via mitogen-and stress-activated protein kinase (MSK-1 and MSK-2) which is activated by the extracellular signal-regulated kinase (ERK) pathway. Histone phosphorylation in the hippocampus is a N-methyl-D-aspartate receptor (NMDAR) dependant reaction where NMDAR have been previously identified to be important in long term potentiation. After a contextual fear learning response, NMDAR causes the phosphorylation of ERK which then in turn phosphorylate the lysine and serine residues on histone H3.1 Furthermore, the ERK pathway also targets acetylation of histone H3, during contextual fear learning study there was a time dependent increase in phosphorylation which coincided with acetylation and phospho-acetylation of both lysine and serine residue, both increase in phosphorylation and acetylation were blocked when NMDAR is inhibited suggesting a potential system where a combination of epigenetic markers are required for the proper control of gene expression.1,8

3.0 Memory consolidation

Previous studies have shown that the initial storage of memory lies in the hippocampus, however this is only temporary unless it can be convert and stored as long term memory in the cortex.3,4,5 Gräff and colleagues studied the effect of various histone modifications including methylation and acetylation and phosphorylation on memory consolidation. Gräff showed that H3S10 phosphorylation (pH3S10), H3K14 acetylation (AcH3K14) and H3K36 trimethylation (3MeH3K36) were significantly increased in the hippocampus of animals 10 minutes after they performed an object recognition task suggesting correlation of histone modifications with short term memory. One day after the recognition task both H3S10 and pH3S10 remain elevated but AcH3k14 showed a dramatic decrease back to its original level and all histone modification were back to its original level after 7 days. These results suggest different modifications play a different role in different type of memory, in this case AcH3k14 is more engaged with recent memory while the other two is more involved in short term memory. In contrast histone modifications in the prefrontal cortex (PFC) regions reached its peak 7 days after the task, this is consistent with previous studies that memory is first established in the hippocampus and later consolidates in the cortex. To further confirm this theory the authors administered staurosporine, C464 and 3-deazaneplanocin to inhibit phosphorylation, acetylation and methylation respectively and show that only long term memory is in fact compromised providing further causal evidence between histone modifications and memory consolidation.4

zif268 is a memory genes that activates during memory formation and consolidation.4,8 Similar to levels of histone modification, zif268 showed an increase in expression in the hippocampus following a recognition task that subsided after 1 day but instead increased expression in the PFC 7 days later. Furthermore, pH3S10, AcH3K14 and 3MeH3K36 modifications showed the exact same level of fluctuation at the promoter region of zif268 both in hippocampus and PFC suggesting that histone modifications is involved in the control of zif268 expression during memory formation.4

Bibliography
  1. Chwang, W. B. (2006). ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learning & Memory, 13(3), 322–328.
  2. Dalton, S. R., & Bellacosa, A. (2012). DNA demethylation by TDG. Epigenomics, 4(4), 459–67.
  3. Day, J. J., & Sweatt, J. D. (2010). DNA methylation and memory formation. Nature Neuroscience, 13(11), 1319–23.
  4. Gräff, J., Woldemichael, B. T., Berchtold, D., Dewarrat, G., & Mansuy, I. M. (2012). Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation. Nature Communications, 3, 991.
  5. Gupta, S., Kim, S. Y., Artis, S., Molfese, D. L., Schumacher, A., Sweatt, J. D., … Lubin, F. D. (2010). Histone Methylation Regulates Memory Formation. The Journal of Neuroscience, 30(10), 3589–3599.
  6. Merschbaecher, K., Haettig, J., & Mueller, U. (2012). Acetylation-Mediated Suppression of Transcription-Independent Memory: Bidirectional Modulation of Memory by Acetylation, 7(9), e45131.
  7. Miller, C. A. (n.d.). DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiology of Learning and Memory, 89(4), 599–603.
  8. Peixoto, L., & Abel, T. (2013). The Role of Histone Acetylation in Memory Formation and Cognitive Impairments. Neuropsychopharmacology, 38(1), 62–76.

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