Decoding the epigenetic language of neuronal plasticity

Abstract

Neurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. These unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. Epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. This review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. We outline the molecular pathways underlying chromatin transitions, propose the presence of an "epigenetic indexing code," and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function.

Figure 1. Genetic versus Epigenetic Control

Regulation of biological processes can be achieved via genetic and epigenetic programs. Variation in genetic information is obtained by mutagenesis of the DNA sequence that irreversibly changes the encoded message. Epigenetic control operates either on DNA, via DNA methylation, or on chromatin. Variation in the chromatin template can be brought about by posttranslational modifications (PTMs; colored beads) added to histones, exchange and replacement of major histones with specialized variants (colored wedges), or ATP-dependent nucleosome remodeling (not depicted), which alters histone:DNA contacts. All of these mechanisms, along with DNA methylation and potential interactions with noncoding RNAs (not depicted), likely act together to bring about the plasticity that helps to define epigenetic phenomena. PTMs of histones occur at highly conserved residues of the N-terminal tails of the core histones (see Figure 3) and include acetylation, methylation, phosphorylation, ubiquitination, etc. Examples of combined DNA methylation and histone modifications have been reported.

Figure 2. Distinct Classes of Chromatin Remodeling Molecules

Specific marks on the N-terminal tails of core histones are PTMs elicited by chromatin remodeling machineries that include a large variety of regulatory molecules, many of which interact physically and functionally. Conceptually, the regulators may be indicated as follows. (1) Writers. These are enzymes such as kinases, HATs, and HMTs that modify specific substrates adding phosphate, acetyl, or methyl groups. (2) Readers. These include a large variety of regulatory proteins that share unique domains implicated in recognizing acetyl or methyl groups. Some other domains, such as BRCT (Manke et al., 2003) and a specific region in 14−3−3 (Macdonald et al., 2005), can be considered as readers of phosphate. Often, “readers” recruit to chromatin additional epigenetic effectors. (3) Erasers. These enzymes include phosphatases, HDACs, and DMTs, which directly remove PTMs.

Figure 3. Multiple Posttranslational Modifications on Histone Tails

The H3 N-terminal tail, here presented as a paradigm of all histone tails, can undergo numerous modifications. Here, only phosphorylation, acetylation, and methylation are indicated. Methylation can be mono-, di-, or trimethyl. The enzymatic machinery that elicits these PTMs is believed to be under the physiological control of neuronal stimuli. Specific combinations of PTMs correspond to selective states of chromatin, either permissive or not for transcription, responsive to damage and stress, or modulated by physiological changes in cellular metabolism.

Figure 4. Dynamic Changes in Histone Modifications in the Hippocampus

Chromatin remodeling occurs in hippocampal neurons of the dentate gyrus 30 min after administering kainic acid (35 mg/kg) to a mouse. Kainate receptors are involved in epileptogenesis and synaptic plasticity. H3S10 phosphorylation in these neurons is induced by stimulation of dopamine, acetylcholine, and glutamate receptors and is often associated with acetylation at H3K14 (Crosio et al., 2003). These events are coupled to transcriptional activation in hippocampal neurons. An antibody that recognizes specifically H3 P-S10 was used.

Figure 5. Signaling Pathways Linking Dopamine to the Circadian Clock

Dopamine controls many brain functions, including roles in behavior and cognition, motor activity, motivation, and reward. Signaling mediated by D2 receptor is envisaged to control chromatin remodeling via modulation of various enzymatic functions. By using either the ERK transduction pathway or the alternative AKT/GSK-3 signaling system, dopamine could control kinases that phosphorylate H3, such as Rsk2 and MSK1, or the enzymatic function of HATs, such as CBP or CLOCK. The GSK-3 kinase is inhibited by lithium and thereby is implicated in the treatment of mood disorders. These regulatory pathways may integrate circadian control, dopamine signaling, and chromatin remodeling.

Figure 6. CLOCK-Mediated Acetylation and Regulation by SIRT1, an NAD⁺-Dependent HDAC

CLOCK acetylates H3 and its dimerization partner BMAL1 to regulate clock-controlled genes. SIRT1 associates with CLOCK and, in response to metabolic changes in intracellular NAD⁺ levels, modulates clock-controlled genes by virtue of its HDAC enzymatic activity. Thus, metabolic, nutritional, and environmental cues modulate the circadian machinery via chromatin remodeling.

Figure 7. Consolidation of Epigenetic Information by Progressive Enzymatic Modifications

Scheme of the proposed step-wise consolidation process of epigenetic information, in which successive and interconnected histone PTMs elicit transition from an “unlocked” chromatin state to a “locked,” fully committed state to either gene activation or silencing. The unlocked state is characterized by dynamic, transient, and charged PTMs, such as phosphorylation and acetylation. The locked state is achieved through noncharged, stable modification of both histones and DNA by methylation. Graded modulation of this process is under the control of intracellular signaling, polymodifications (polyubiquitylation, etc.), and microRNA pathways.