Distinct nuclear compartment-associated genome architecture in the developing mammalian brain

In the nucleus, specific stretches of DNA are 'anchored' to distinct membrane-less compartments that harbor gene regulatory function. Using GO-CaRT, the authors discovered unique aspects of genome architecture in neural precursors in vivo, providing new insights into brain development and disease. Nuclear compartments are thought to play a role in three-dimensional genome organization and gene expression. In mammalian brain, the architecture and dynamics of nuclear compartment-associated genome organization is not known. In this study, we developed Genome Organization using CUT and RUN Technology (GO-CaRT) to map genomic interactions with two nuclear compartments-the nuclear lamina and nuclear speckles-from different regions of the developing mouse, macaque and human brain. Lamina-associated domain (LAD) architecture in cells in vivo is distinct from that of cultured cells, including major differences in LADs previously considered to be cell type invariant. In the mouse and human forebrain, dorsal and ventral neural precursor cells have differences in LAD architecture that correspond to their regional identity. LADs in the human and mouse cortex contain transcriptionally highly active sub-domains characterized by broad depletion of histone-3-lysine-9 dimethylation. Evolutionarily conserved LADs in human, macaque and mouse brain are enriched for transcriptionally active neural genes associated with synapse function. By integrating GO-CaRT maps with genome-wide association study data, we found speckle-associated domains to be enriched for schizophrenia risk loci, indicating a physical relationship between these disease-associated genetic variants and a specific nuclear structure. Our work provides a framework for understanding the relationship between distinct nuclear compartments and genome function in brain development and disease.

Automated summary

This study utilized GO-CaRT technology to investigate genome architecture in neural precursors, revealing the relationship between LAD architecture and regional identity of neural precursor cells, as well as identifying transcriptionally highly active sub-domains within LADs. Additionally, the study found speckle-associated domains to be enriched for genetic loci associated with schizophrenia risk.