Chromatin Structure and Dynamics: Focus on Neuronal Differentiation and Pathological Implication

Abstract

Chromatin structure is an essential regulator of gene expression. Its state of compaction contributes to the regulation of genetic programs, in particular during differentiation. Epigenetic processes, which include post-translational modifications of histones, DNA methylation and implication of non-coding RNA, are powerful regulators of gene expression. Neurogenesis and neuronal differentiation are spatio-temporally regulated events that allow the formation of the central nervous system components. Here, we review the chromatin structure and post-translational histone modifications associated with neuronal differentiation. Studying the impact of histone modifications on neuronal differentiation improves our understanding of the pathophysiological mechanisms of chromatinopathies and opens up new therapeutic avenues. In addition, we will discuss techniques for the analysis of histone modifications on a genome-wide scale and the pathologies associated with the dysregulation of the epigenetic machinery.

Keywords: acetylation; chromatin; chromatinopathies; epigenetics; histone modification; methylation; neuronal differentiation.

Figure 1

Overview of the different levels of DNA compaction. The first higher-order structure of the chromatin is the nucleosome, which is composed of 145–147 bp of DNA wrapped around a H3/H4 tetramer and two H2A/H2B dimers. The histone H1 linker binds DNA fragments that link two nucleosomes to form the chromatosome. The addition of H1 promotes internucleosomal interactions and the formation of the 30 nm chromatin fiber. The highest level of DNA compaction is the metaphasic chromosome, observable during cell division.

Figure 2

Structure of a nucleosome and main sites of methylation and acetylation in histones. Post-translational modifications of the histones are mostly performed on the amino-terminal tails of the histones accessible to the epigenetic writer and eraser. Acetylated residues are in pink and methylated ones are in green.

Figure 3

Overview of histone acetylation and deacetylation and their impact on chromatin structure. A histone acetylation reader protein is shown in dark blue. Bromodomain-containing proteins can bind to acetylated histones.

Figure 4

Overview of the mechanism of histone methylation by a methyltransferase. S-adenosyl-L-methionine (SAM) is the methyltransferase cofactor. Following methylation, S-adenosylhomocysteine (SAH) is released and the methylated moiety is attached to Nε-Lysine. A methylation reader is represented in purple and corresponds, for example, to a chromodomain or tudor domain protein.

Figure 5

Major histone marks found at active enhancers, promoters and gene bodies. The arrow represents the transcription start site. H3K27ac is found both at active enhancers and promoters. H3K4me1 is enriched in enhancer regions whereas H3K4me3 is found mostly at promoters. Active gene regions are enriched in H3K36me3, H3K79me2 and H3K79me3.

Figure 6

Neural stem cells give rise to the neuronal and glial lineage by passing through the neural progenitor stage. Neurogenesis occurs in the embryonic brain but also in the adult brain.