Chromatin Regulation of Neuronal Maturation and Plasticity

Abstract

Neurons are dynamic cells that respond and adapt to stimuli throughout their long postmitotic lives. The structural and functional plasticity of neurons requires the regulated transcription of new gene products, and dysregulation of transcription in either the developing or adult brain impairs cognition. We discuss how mechanisms of chromatin regulation help to orchestrate the transcriptional programs that underlie the maturation of developing neurons and the plasticity of adult neurons. We review how chromatin regulation acts locally to modulate the expression of specific genes and more broadly to coordinate gene expression programs during transitions between cellular states. These data highlight the importance of epigenetic transcriptional mechanisms in postmitotic neurons. We suggest areas where emerging methods may advance understanding in the future.

Keywords: DNA methylation; chromatin structure; enhancer; neuroepigenetics; neuronal maturation; plasticity.

Figure 1

Multiple levels of chromatin regulation interact to coordinate gene expression in developing neurons. As neural progenitor cells make the transition to become mature postmitotic neurons, there is: (A) increased accumulation of DNA methylation (M) mainly in the form of mCpA with no change in mCpG; (B) dynamic modification of post-translational modifications on histones (M, methylation; Ac, acetylation) by enzymes such as histone acetyltransferases (HATs) that allow both increases and decreases in chromatin accessibility and subsequent changes in transcription factor (TF) binding at specific gene regulatory elements; and (C) large-scale changes in chromatin configuration and nuclear architecture that initiate interactions of different DNA sequences with the nuclear lamina (repression, red) or transcriptional factories (activation, green). These three different scales in chromatin regulation can result in unique and cell-specific gene expression programs, appropriate for every stage of neuronal development.

Figure 2

Histone modifications that modulate neuronal activity-dependent gene transcription. (A) Membrane depolarization-induced H3K27ac at distal enhancer regions and gene promoters is associated with the induction of activity-dependent gene transcription and the formation of stable loops between active enhancer regions and the promoters of their target genes. (B) Turnover of histone proteins results in regulated deposition of the variant histones H3.3 via Hira/DaXX and H2A.Z via the NuRD complex. H3.3 turnover facilitates the transcription of membrane depolarization-induced late-response genes whereas H2A.Z deposition at gene promoters represses the transcription of activity-dependent plasticity genes. (C) Neuronal activity induces changes in chromatin accessibility. Activity-induced opening of chromatin at distal regulatory elements is mediated via the recruitment of Fos and other AP-1 element binding proteins. TF, transcription factor; Ac, histone acetylation; CBP, Creb Binding Protein; CHD4, Chromodomain protein 4.