Cell-type-specific 3D-genome organization and transcription regulation in the brain

3D organization of the genome plays a critical role in regulating gene expression. How 3D-genome organization differs among different cell types and relates to cell type–dependent transcriptional regulation remains unclear. Here, we used genome-scale DNA and RNA imaging to investigate 3D-genome organization in transcriptionally distinct cell types in the mouse cerebral cortex. We uncovered a wide spectrum of differences in the nuclear architecture and 3D-genome organization among different cell types, ranging from the size of the cell nucleus to higher-order chromosome structures and radial positioning of chromatin loci within the nucleus. These cell type–dependent variations in nuclear architecture and chromatin organization exhibit strong correlations with both the total transcriptional activity of the cell and transcriptional regulation of cell type–specific marker genes. Moreover, we found that the methylated DNA binding protein MeCP2 promotes active-inactive chromatin segregation and regulates transcription in a nuclear radial position–dependent manner that is highly correlated with its function in modulating active-inactive chromatin compartmentalization.