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.