Abstract
In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activity-dependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.
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Acknowledgements
This work was supported by the US National Institutes of Health (National Institute on Aging grants AG051807, AG050787 and AG054349; National Institute of Mental Health grant MH101491; and National Institute on Drug Abuse grant DA025922). Initial illustrations were designed by P. Schiffmacher of Schiffmacher Illustration & Design. The authors thank A. López and T. Hemstedt for their intellectual contributions to this Review.
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Nature Reviews Neuroscience thanks S. Bonn and F. Lubin, and the other anonymous reviewer(s), for their contribution to the peer review of this work.
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R.R.C. and M.A.W. researched data for the article; contributed substantially to discussion of content; and wrote, reviewed and edited the manuscript before submission.
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Glossary
- Epigenome
-
The collective combination of chemical modifications and proteins that interact with the human genome. The epigenome is dynamically regulated, serves as a signal-integration platform and is unique to each individual.
- Histone modification
-
A post-translational modification — such as acetylation, methylation or phosphorylation — of a histone, a protein that interacts with nuclear DNA and helps to condense genomic DNA into chromatin.
- Histone variant exchange
-
Exchange of variants of the canonical histone proteins (namely, H2A, H2B, H3 and H4). Histone variants include H2AZ and H3.3 and can generate specialized chromatin domains and alter the DNA accessibility and thus gene expression.
- Nucleotide modification
-
Epigenetic modification (mark) of nucleotide bases. For example, DNA methylation involves the attachment of a methyl group to the C5 position of cytosine (5mC). 5-Hydroxymethylcytosine (5hmC) seems to be more abundant in the brain.
- Chromatin remodelling
-
In general, the rearrangement and regulation of chromatin (DNA and associated proteins) by various mechanisms, including modification (for example, histone modification) and nucleosome remodelling.
- Epigenetic priming
-
Stable epigenetic changes (DNA modifications and exchange of transcriptional cofactors and histone variants) produced by exposure to salient stimuli that induce neuronal stimulation; these changes permit efficient transcription of memory-related genes upon re-exposure and reactivation.
- Histone acetyltransferase
-
(HAT). An enzymes that catalyses the transfer of an acetyl group from acetyl-CoA to the ε-amino group of a histone lysine residue on a histone protein.
- Rubinstein–Taybi syndrome
-
A condition characterized by moderate to severe intellectual disability, short stature, distinctive facial features and broad thumbs and first toes. It is often caused by CREBBP (also known as CBP) mutations.
- Histone deacetylases
-
(HDACs). Enzymes that remove acetyl groups from lysine residues on DNA. Acetyl groups help to neutralize the positive charge of histones and/or serve as binding sites for bromodomain-containing proteins.
- Long-term facilitation
-
(LTF). A form of long-term synaptic plasticity observed in Aplysia californica.
- Ten-eleven translocation enzymes
-
(TETs). Enzymes that convert 5-methylcytosine (5mC) DNA marks to 5-hydroxymethylcytosine (5hmC), which is enriched within gene bodies, promoters and transcription-factor-binding regions and may influence gene expression.
- Nucleosome-remodelling complexes
-
(NRCs). Large protein complexes that, through the activity of ATP-dependent enzymes, alter histone–DNA interactions, disassemble or assemble nucleosomes, exchange histone variants or slide or reposition nucleosomes.
- Histone code hypothesis
-
A hypothesis that posits that specific patterns of epigenetic modifications regulate specific gene expression networks for defined cell functions.
- Early-phase LTP
-
(E-LTP). In this context, a form of potentiation that is dependent on covalent protein modifications, yet independent of gene expression. It is transient and short-lived (generally on the order of tens of minutes in slices).
- Late-phase LTP
-
(L-LTP). In this context, a form of potentiation that is dependent on transcription and translation. It is long-lasting (generally on the order of hours in slices and hours to days in vivo).
- Extinction
-
Weakening of a conditioned response owing to long or repeated trials of memory retrieval in which the conditioned stimulus is removed. Extinction is hypothesized to result from the formation of new memories.
- Reconsolidation
-
The re-encoding and re-stabilization of a memory after reactivation, during which time the memory is hypothesized to be labile and vulnerable to manipulation.
- Remote memories
-
Here, memories that were encoded a long time previously and that have since become independent of the hippocampus and dependent on cortical regions of the brain (through a process sometimes termed systems consolidation).
- Epigenetic hypothesis of age-related cognitive impairments
-
A hypothesis proposing that the repression of chromatin and alterations in the expression of synapse-related genes lead to cognitive impairment in ageing brains.
- Extra-coding RNAs
-
A form of non-coding, sense-strand RNA that is non-polyadenylated, encoded by a portion of DNA that overlaps the boundaries of another gene.
- Enhancer RNAs
-
A form of non-coding RNA transcribed from active enhancers. They can control mRNA transcription, challenging the idea that enhancers are merely sites of transcription factor assembly.
- E3 ubiquitin ligase
-
A protein that facilitates the interaction of a target (or substrate) protein with an ubiquitin-conjugating E2 enzyme to enable the transfer of ubiquitin to the target protein.
- Synaptophysin
-
A synaptic vesicle membrane protein that is ubiquitously expressed throughout the brain and has a role in synapse formation.
- INTACT
-
(Isolation of nuclei tagged in specific cell types). A method to isolate nuclei tagged in specific cell types for further examination for specific proteins or RNAs or high-throughput sequencing.
- TRAP
-
(Translating ribosome affinity purification). A ribosome-tagging method in which a fusion protein binds ribosomal proteins and immunoprecipitation purification processes isolate biologically relevant mRNA transcripts.
- Assay for transposase-accessible chromatin using sequencing
-
(ATAC-seq). A method for mapping genome-wide chromatin accessibility. A transposase inserts sequencing adaptors into accessible regions of chromatin, before adaptor-ligated DNA fragments are sequenced.
- Zinc-finger proteins
-
(ZFPs). A large family of transcription factors with finger-like DNA-sequence-specific domains. Fusion of a DNA-binding domain specific for an 18–20 bp genomic locus to a chromatin-modifying enzyme enables targeted epigenetic regulation.
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Campbell, R.R., Wood, M.A. How the epigenome integrates information and reshapes the synapse. Nat Rev Neurosci 20, 133–147 (2019). https://doi.org/10.1038/s41583-019-0121-9
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DOI: https://doi.org/10.1038/s41583-019-0121-9
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