Regulation of chromatin structure in memory formation

doi:10.1016/j.conb.2009.05.011

Current Opinion in Neurobiology

Volume 19, Issue 3, June 2009, Pages 336-342

https://doi.org/10.1016/j.conb.2009.05.011 Get rights and content

This brief review focuses on the role of epigenetic mechanisms in plasticity and memory formation, and their identification as targets of activity-dependent regulation in neurons. Epigenetic modifications of chromatin, namely post-translational modifications of nuclear proteins and covalent modification of DNA, result in potent regulation of gene readout. Recent data have demonstrated that epigenetic mechanisms play a significant role in regulating synaptic plasticity and memory. In this review, we focus on this theme, describing some basic background concerning epigenetic molecular mechanisms, and describing recent results concerning plasticity and memory formation. As an understanding of these novel mechanisms of transcriptional regulation promises to invigorate many areas of investigation, we end by speculating upon some of the open questions ripe for discovery.

Section snippets

Introduction — an epigenetic code for memory?

Recent studies have demonstrated that nuclear targets of neuronal signaling pathways, in particular the histone proteins and DNA that comprise the core chromatin particle, are also an integral component of memory processes (reviewed in [1, 2, 3]). We and others have proposed that an epigenetic code might be involved in memory formation, whereby specific patterns of post-translational histone modifications and DNA methylation might help encode the salience of cell-surface signals and their

Epigenetic histone marks

Histones are highly basic proteins that organize DNA within the nucleus. The interaction between histones, which form the core of the chromatin particle, and DNA, is mediated in part by the N-terminal tail of histone proteins. One can imagine chromatin as a core of eight histone proteins (histones 2A, 2B, 3, and 4, with two copies of each molecule) with DNA wrapped around similar to twine on a spool. Structural studies indicate the N-terminal tails of histones protrude beyond the DNA and are

Covalent modification of DNA — cytosine methylation

The second major mechanism whereby the genome can be epigenetically marked is DNA methylation (see [20, 21] for a more detailed treatment of this mechanism). Methylation of DNA is a direct chemical modification of a cytosine side-chain that adds a –CH₃ group through a covalent bond (Figure 1c). Methylation of DNA is catalyzed by a class of enzymes known as DNA methyltransferases (DNMTs) [20, 21]. DNMTs transfer methyl groups to cytosine residues, specifically at the 5th position of the

Epigenetic marking of histones in memory

A diverse series of studies have demonstrated memory formation is associated with epigenetic marking of the genome. For example, contextual fear memory formation in rodents is associated with acetylation of hippocampal histone H3 [4, 30, 31••]. This epigenetic marking requires NMDA-receptor-dependent synaptic transmission and the ERK/MAPK signaling cascade in the hippocampus, as does the fear conditioning memory itself [31••, 32]. This is one specific example demonstrating epigenetic tagging of

DNA methylation in memory

Studies have also begun to investigate the capacity of DNA methylation to regulate synaptic plasticity and memory in adult animals [31••, 36, 37•, 38, 39••]. Inhibitors of DNMTs alter DNA methylation in adult CNS tissue and block hippocampal long-term potentiation (LTP) [36, 37•, 38]. DNMT inhibition blocks hippocampus-dependent memory formation in a contextual fear conditioning paradigm [31••, 39••]. Data also demonstrate fear conditioning is associated with rapid methylation and

Summary and speculations

Thus far we have presented an emerging new view of the epigenome and its role in regulating memory formation. Indeed, this is a rapidly expanding area in neurobiology and studies are being published at a rapid pace demonstrating that epigenetic mechanisms are involved in mediating diverse experience-driven changes in the CNS. The effects of such changes are manifest at the molecular, cellular, circuit, and behavioral levels. These diverse observations support the view that the epigenome resides

References and recommended reading

Paper of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We wish to thank Felecia Hester for her assistance in preparing this review. We would also like to apologize to the colleagues whose work we could not cite because of space limitations. This work was funded by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, Civitan International, the Rotary Clubs CART fund, and the Evelyn F. McKnight Brain Research Foundation.

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View full text

Regulation of chromatin structure in memory formation

Section snippets

Introduction — an epigenetic code for memory?

Epigenetic histone marks

Covalent modification of DNA — cytosine methylation

Epigenetic marking of histones in memory

DNA methylation in memory

Summary and speculations

References and recommended reading

Acknowledgements

Neuron

Behav Brain Res

Biol Psychiatry

J Biol Chem

Neuron

Neuron

Neuron

Nat Rev Genet

Nature

Biol Psychiatry

Nucleic Acids Res

Mol Cell

PLoS ONE

Combinatorial chromatin modifications and memory storage: a code for memory?

Learn Mem

Translating the histone code

Science

Crystal structure of the nucleosome core particle at 2.8 Å resolution

Nature

The language of covalent histone modifications

Nature

Structure and function of histone acetyltransferases

Cell Mol Life Sci

Transgenic mice expressing an inhibitory truncated form of p300 exhibit long-term memory deficits

Learn Mem

Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation

J Neurosci

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

Curr Opin Pharmacol

Therapeutic application of histone deacetylase inhibitors for central nervous system disorders

Nat Rev Drug Discov

Epigenetics, DNA methylation, and chromatin modifying drugs

Annu Rev Pharmacol Toxicol

Diversity in the Sir2 family of protein deacetylases

J Leukoc Biol

DNA methylation patterns and epigenetic memory

Genes Dev