Scientific Understanding of Consciousness
Chromatin Plasticity and Brain Function
Nature Volume: 465, Pages: 728–735 (10 June 2010)
Brain function and chromatin plasticity
Howard Hughes Medical Institute, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
The characteristics of epigenetic control, including the potential for long-lasting, stable effects on gene expression that outlive an initial transient signal, could be of singular importance for post-mitotic neurons, which are subject to changes with short- to long-lasting influence on their activity and connectivity. Persistent changes in chromatin structure are thought to contribute to mechanisms of epigenetic inheritance. Recent advances in chromatin biology offer new avenues to investigate regulatory mechanisms underlying long-lasting changes in neurons, with direct implications for the study of brain function, behaviour and diseases.
One of the most intriguing and fundamental properties of brain function is the ability to sustain long-term changes in patterns of neuronal activity, a phenomenon broadly defined as memory. Memory can last from minutes to years, suggesting the existence of multiple mechanisms for altering neuronal function and for generating short- to long-lasting changes in the brain. The precise mechanisms underlying memory formation, and the associated plasticity of neuronal function, have been subject to intense investigation at the molecular, cellular and neuronal network levels and are likely to involve a combination of changes in gene expression, protein synthesis, and cellular and anatomical structure.
In recent years, there has been an extensive search for gene regulatory mechanisms that respond on the short timescale associated with memory formation while persisting over the long timescale for which memory can last. This has prompted much interest in the process of epigenetic inheritance. Epigenetic changes are defined as alterations in gene expression that are self-perpetuating in the absence of the original signal that caused them. The idea of a persistent change in gene expression being triggered by a transient event is intuitively parallel to the long-term effects thought to be involved in memory.
A major class of epigenetic mechanism is thought to involve persistent changes in chromatin structure. Most, if not all, transcriptional regulatory events cause changes to chromatin structure and composition, which result from the recruitment of chromatin-modifying enzymes by transcription factors and by the transcriptional machinery itself. The recent realization that most genes associated with mental retardation (learning disability) affect chromatin-remodelling processes, together with the identification of chromatin alterations that are involved in the process of neuronal plasticity and in long-lasting changes in brain function, has brought chromatin biology to the forefront of molecular neuroscience and neuropathology.
This Review assesses the contribution of various chromatin-remodelling events to long-lasting changes in brain function based on representative examples in the recent literature.
Sustained changes in neuronal activity affect chromatin
Neuronal activity induces changes in gene expression that are essential for establishing and maintaining long-term neuronal plasticity in the adult brain. Consequently, and perhaps not unexpectedly, the promoter regions of genes involved in neuronal plasticity undergo activity-dependent alteration in chromatin composition, and a growing number of reports describe changes in chromatin states, particularly in DNA methylation and histone marks, that are associated with long-term plasticity.
DNA methylation and brain activity
The methylation of cytosine nucleotides in DNA to form 5-methylcytosine, which in mammalian cells is mainly confined to CpG dinucleotides, is viewed as the most stable and long-lasting chromatin modification. DNA methylation is known to have a role in the constitutive silencing of chromatin regions, the inactivation of one of the X chromosomes in females, the imprinting of parental alleles (see the subsection 'Genomic imprinting'), and the silencing of retroviral genes and other individual genes. The precise mechanisms by which DNA methylation marks are set, maintained and erased, however, are the subject of much debate
Histone modifications and neuronal plasticity
Molecular analysis of signalling pathways underlying neuronal plasticity has identified alterations of histone marks, particularly histone acetylation, in transcriptional units induced by neuronal activity, and has implicated histone-modifying enzyme complexes in memory formation. These findings have raised interesting mechanistic questions, as well as new ideas for the design of drugs targeted at memory impairment.
Sensory experience and resultant neuronal activation lead to depolarization and calcium influx into the postsynaptic cell, which in turn triggers signals orchestrating short- and long-term changes in synaptic strength. The induction of specific activity-dependent transcriptional programs has been shown to have a key role in experience-dependent, long-term neural plasticity. In-depth studies have led to the characterization of a prototypical signalling pathway that is evolutionarily conserved in Aplysia, Drosophila and mice and by which extracellular stimuli are transformed into changes in activity-dependent gene expression. Gene regulation by CREB, originally identified as binding to the cyclic-AMP response element (CRE) and the calcium-dependent response element of the genes encoding somatostatin and c-FOS, respectively, as well as mediating long-term synaptic potentiation in Aplysia, is particularly central to the generation of many forms of long-term memory. After postsynaptic depolarization and calcium entry, activated CREB binds to the CRE in the promoter region of activity-induced genes such as the immediate early gene c-Fos and the neurotrophin Bdnf and, in conjunction with different combinations of other factors, orchestrates long-term activity-induced changes in gene expression.
The increasingly large number of experimental data associating long-term changes in brain activity with alterations in chromatin raises several fundamental issues. Histone post-translational modifications and other chromatin-remodelling events are expected mechanisms of gene regulation in any cellular system undergoing long-lasting changes.
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