Chromatin remodeling in neural development and plasticity
Introduction
Recently, we published a review describing how different epigenetic mechanisms contribute to neural cell fate specification [1]. We focused on the role of DNA methylation, histone modifications (such as acetylation and methylation) and regulatory noncoding RNAs. In this review, we expand on the idea that chromatin remodeling and epigenetic mechanisms may regulate rapid changes in brain function, which is particularly important during the postnatal period when infants explore their world. Postnatal and adult neurogenesis can be divided into three stages: first, self-renewal, fate specification (into neurons and glia) and survival of neural precursor cells; second, migration and connection of newborn neurons with pre-existing neurons; and third, reorganization in the synaptic connectivity between newborn and pre-existing neurons driven by sensory experience. Epigenetic alterations leading to chromatin remodeling could provide a coordinated system of regulating gene expression at each stage of neurogenesis. Interestingly, disruption of epigenetic mechanisms leading to dysregulation of gene expression results in a number of syndromes associated with mental retardation (e.g. ATR-X, Fragile X, Rett, Rubinstein-Taybi, ICF and Angelman; reviewed in [2]). Why the development and function of the CNS seem to be particularly sensitive to epigenetic changes and the exact connection between epigenetic regulation and brain function remain obscure. Here we discuss new insights regarding chromatin-based mechanisms of neural development and plasticity in both normal and disease states.
Section snippets
Chromatin structure and the role of histone modifications
Many studies in recent years have focused on the role of chromatin structure, particularly the covalent modifications that take place on histones, in controlling cellular identity and mediating heritable changes in gene expression (reviewed in [3]). One of the best-characterized histone modifications to date is lysine acetylation, which is mediated by two groups of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Figure 1). HATs induce acetylation of N-terminal
Context-dependent gene regulation by the NRSF complex
During development, telencephalic neuroepithelial cells first undergo limited expansion, mostly through symmetric divisions, and then undergo neurogenesis, chiefly involving asymmetric divisions (reviewed in [25]). Toward the end of neurogenesis, cortical progenitors switch back to symmetric divisions and give rise to astrocytes and oligodendrocytes. A vast array of transcriptional repressors and activators underlies the sequential stages of neuronal and glial fate specification (reviewed in [26
An emerging role for SWI/SNF chromatin remodeling complexes in neurogenesis
One of the first chromatin remodeling complexes identified, the SWI/SNF family of chromatin remodeling proteins, uses ATP hydrolysis to disrupt histone–DNA associations (reviewed in [42]). SWI/SNF complexes interact with HATs or HDACs and/or sequence-specific transcription factors to activate or repress target genes. Chromodomain proteins, which possess the ATPase domain found in SWI/SNF proteins, are also recruited by polycomb repressors, and are involved in silencing gene expression from
Epigenetic control of neural plasticity, learning and memory
Epigenetic mechanisms spanning diverse areas, such as histone modifications, polyADP-ribosylation, DNA methylation and even retrotransposition, have been linked with changes in neural plasticity and long-term memory (reviewed in [51]). Previously, studies of long-term plasticity in Aplysia sensory-motor synapses have revealed a role for HDAC5 and histone acetylation at the promoter of the immediate early gene C/EBP when stimuli producing long-term facilitation or long-term depression were
Conclusions
One of the biggest mysteries regarding brain function is how specific instructions for cellular and tissue patterning are laid out without preventing a large degree of plasticity being retained in order for the brain to respond to the changing environment. The brain must be able to relay environmental information down to the cellular and molecular level where it can effect changes in gene expression. Epigenetic and chromatin modifications of target genes in response to variations in
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank ML Gage for editorial assistance and J Simon for graphics.
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