Epigenetics and the timing of neuronal differentiation

Abstract

Epigenetic regulation of the genome is required for cell-type differentiation during organismal development and is especially important to generate the panoply of specialized cell types that comprise the brain. Here, we review how progressive changes in the chromatin landscape, both in neural progenitors and in postmitotic neurons, orchestrate the timing of gene expression programs that underlie first neurogenesis and then functional neuronal maturation. We discuss how disease-associated mutations in chromatin regulators can change brain composition by impairing the timing of neurogenesis. Further, we highlight studies that are beginning to show how chromatin modifications are integrated at the level of chromatin architecture to coordinate changing transcriptional programs across developmental including in postmitotic neurons.

Figure 1:. Dynamic changes in the distribution of DNA and histone methylation orchestrate gene expression during neuronal maturation.

The figure represents data from references [–, –28] and shows a single neuronal gene (purple) that shows induced transcription (enlarging green arrow) over developmental time. Top panels, at megabase scale, neuronal genes may be embedded within regions of DNA methylation (orange) that are selectively depleted over neuronal genes across time to form methylation “valleys” as the gene becomes active. A subset of developmentally activated genes are also embedded within regions that experience distal increases in H3K27me3 (red) at non-promoter/enhancer regions. Bottom panels, at the scale of a single gene, changes in the relative proportion of poised (H3K4me1, blue), active (H3K4me3, green), and repressive (H3K27me3, red) histone modifications are associated with developmental gene activation. Activity-regulated genes may be further poised by H3K27me3 deposition across the gene body.