3D Genome Plasticity in Normal and Diseased Neurodevelopment

Abstract

Non-random spatial organization of the chromosomal material inside the nuclei of brain cells emerges as an important regulatory layer of genome organization and function in health and disease. Here, we discuss how integrative approaches assessing chromatin in context of the 3D genome is providing new insights into normal and diseased neurodevelopment. Studies in primate (incl. human) and rodent brain have confirmed that chromosomal organization in neurons and glia undergoes highly dynamic changes during pre- and early postnatal development, with potential for plasticity across a much wider age window. For example, neuronal 3D genomes from juvenile and adult cerebral cortex and hippocampus undergo chromosomal conformation changes at hundreds of loci in the context of learning and environmental enrichment, viral infection, and neuroinflammation. Furthermore, locus-specific structural DNA variations, such as micro-deletions, duplications, repeat expansions, and retroelement insertions carry the potential to disrupt the broader epigenomic and transcriptional landscape far beyond the boundaries of the site-specific variation, highlighting the critical importance of long-range intra- and inter-chromosomal contacts for neuronal and glial function.

Keywords: 3D genome; 4D nucleome; Hi-C; brain; chromosomal conformations; cis-regulatory domain; neurodevelopment; neuropsychiatric disorder; non-coding DNA.

Figure 1

Hi-C Chromosomal contact (DNA-DNA proximity) mapping. (A) Basic principle. DNA-DNA proximity mappings typically use restriction digest followed by proximity religation techniques to capture chromosomal contacts. (B) basic building blocks of the 3D genome in the kilo- and megabase range. (C) chrom3D in silico model of topologically associated domains (TADs) [11,12], 1 ball = 1 TAD, TADs from same chromosome share the same color. The 4D nucleome is a concept for comprehensive, integrative analysis of the nucleus across time, including changes during differentiation.

Figure 2

Changes to 3D genome structure in neuropsychiatric disease. (A) Schematic representation of changes to the FMR1 locus in fragile X syndrome (FXS). In FXS, normal TAD structure (shown on the left, CTRL) is disrupted. This change to TAD structure is associated with increased H3K9me3 levels and deceased CTCF binding across the disrupted region. In FXS, the FMR1 locus also has increased trans interactions with multiple other chromosomes and decreased expression. (B) Schematic showing changes to CRDs in schizophrenia (SCZ). Two CRDs are shown within one TAD, one of the CRDs (shown in red) has lower H3K27ac levels in SCZ as compared to health controls (CTRL). This CRD contains genes associated with SCZ risk in GWAS studies. The other CRD is unchanged in SCZ (shown in blue).