Histone acetylation: molecular mnemonics on the chromatin

Key Points

  • Histone acetylation is an epigenetic modification that is unequivocally associated with increasing the propensity for gene transcription. As gene transcription is a crucial feature of long-lasting forms of memories, increments in histone acetylation generally favour learning and memory, and can be considered molecular memory aids.

  • Histone acetylation readily responds to neuronal activity in terms of neuronal depolarization and synaptic plasticity. So far, two pathways that mediate this response have been identified: the mitogen-activated protein kinase (MAPK) pathway and the dissociation of histone deacetylase 2 (HDAC2) from the chromatin.

  • A reduction in histone acetylation has been causally implicated in memory impairment associated with neurodegeneration, ageing and neurodevelopment disorders such as Rubinstein–Taybi syndrome. From these studies, a gain-of-function of HDAC2 and a loss-of-function of the histone acetyl transferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP) emerge as chief culprits.

  • The reduction of histone acetylation can be counteracted by the use of small molecule inhibitors of HDACs, so-called HDAC inhibitors (HDACis). Several HDACis have already been proven successful in rescuing cognitive deficits in animal models of neurodegeneration, Alzheimer's disease, ageing, and Rubinstein–Taybi syndrome, and might thus constitute a new template for pharmacological strategies against cognitive impairments.

  • Although their precise mode of action is still not fully characterized, HDACis might act through a process called epigenetic priming, a term originally used in cancer research. Epigenetic priming refers to a support-only mode of action of HDACis, whereby HDACis alone have little effect (on histone acetylation and gene transcription), but when applied in conjunction with ongoing treatments that increase gene expression programmes, HDACis further potentiate them.

  • concept of epigenetic priming can be applied to neuroplasticity as well, in that HDACs would further support neuronal activity-driven gene expression programmes while having little or no effect on genes with constant rates of transcription.

Abstract

Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.

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Figure 1: The complexity of the epigenetic code in the brain.
Figure 2: Neuronal activity induces histone acetylation.
Figure 3: The upregulation of HDAC2 in pathological conditions and its relation to cognitive impairment.
Figure 4: Epigenetic priming.

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Acknowledgements

We thank S. Jemielity and A. Mungenast for critical reading of the manuscript and acknowledge support from a Bard Richmond grant to J.G., and the US National Institutes of Health (grants, NS078839 and NS51874) to L.-H.T. L.-H.T. is an investigator of the Howard Hughes Medical Institute.

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Glossary

Histone proteins

Basic proteins with a globular core and loosely structured N- and C-terminal tails that form part of the chromatin. Doublets of the four core histones H2A, H2B, H3 and H4 constitute a histone octamer, which is wrapped around by DNA to form the nucleosome. Post-translational histone modifications modulate the compaction of the DNA around histones and thereby the three-dimensional chromatin structure.

Histone deacetylase inhibitors

(HDACis). Small molecules that inhibit the activity of HDACs, most of them by binding to the HDAC catalytic domain.

Synaptic plasticity

The ability of a synapse to change in strength, which is considered to be a cellular correlate of learning and memory.

Long-term facilitation

(LTF). Transcription-dependent facilitation of electrical transmission across synapses.

Long-term depression

(LTD). Transcription-dependent deterioration of electrical transmission across synapses.

Long-term potentiation

(LTP). An increase in synaptic transmission efficiency as a result of presynaptic high-frequency stimulation.

Fear conditioning

A form of associative learning in which an aversive stimulus (for example, an electric shock) is paired with a neutral context (for example, a chamber) or neutral stimulus (for example, a tone), resulting in the expression of fear responses to the originally neutral context or stimulus in the absence of the aversive stimulus.

Latent inhibition

A decrease of the conditioned response in an associative memory task when the conditioned stimulus is presented alone before the conditioning session.

Consolidation

A time-limited process that allows newly acquired memories to be stabilized and permanently stored.

Reconsolidation

A time-limited process that allows reactivated memories to be updated with new information and to be stored in a modified form.

Object location memory

Memory for an object's location that is measured by taking advantage of rodents' natural propensity to explore novel objects. The time spent with a novel versus a familiar object serves as an indicator of the memory strength. In object location, the novelty is given by a change in location of a familiar object.

Object recognition memory

The ability to recognize an object as familiar rather than novel. It is measured in a similar way to object location memory but with the novelty given by presenting the animal with an object that is unfamiliar but in the same location..

Fear memory extinction

A decline in conditioned fear responses when there is a reduction in the predictive value of the conditioned stimulus, for example, through repetitive exposure to the conditioned stimulus without the aversive association.

Alzheimer's disease

(AD). The most common type of neurodegenerative dementia. Patients often show impairments in learning and memory. The disease's neuropathology includes neuron loss in the cerebral cortex and in several subcortical regions and the presence of aggregates in the forms of plaques (containing amyloid-β) and neurofibrillary tangles (containing hyperphosphorylated tau).

Braak and Braak stages

A way to categorize the severity of Alzheimer's disease (AD) according to the extent of tau pathology post-mortem. In BB stages I/II (mild AD), tau pathology is mainly restricted to the entorhinal cortex. In stages III/IV (moderate AD), tau pathology has spread to the hippocampal formation and subcortical nuclei. In stages V/VI (severe AD), tau pathology affects the entire brain.

Huntington's disease

(HD). A neurodegenerative disease that is characterized by progressive loss of movement coordination, muscular atrophy and cognitive decline. It is caused by mutations in the huntingtin gene that lead to abnormally high repetitions of the triplet CAG at its 5′-coding region.

Fragile X syndrome

A common form of neurodevelopmental mental retardation caused by unusual trinucleotide expansions and subsequent gene silencing of fragile X mental retardation 1 (FMR1) or FMR2.

Amyotrophic lateral sclerosis

(ALS). A progressive neurological disease that is associated with the degeneration of central and spinal motor neurons. This neuron loss causes muscles to weaken, leading to paralysis. About 90% of all ALS cases are sporadic, the remaining 10% being caused by genetic mutations, for example, in superoxide dismutase 1 (SOD1).

Rubinstein–Taybi syndrome

A monogenic neurodevelopmental disorder caused by mutations in the gene coding for the histone acetyltransferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP). The disease is characterized by skeletal and facial abnormalities, and varying degrees of mental retardation.

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Gräff, J., Tsai, L. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14, 97–111 (2013). https://doi.org/10.1038/nrn3427

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