The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on 3D epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal activity-regulated genes, thus influencing their expression. It also alters A/B compartments, Topologically Associating Domains and Frequently Interacting Regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence and schizophrenia. Our data establish SATB2 as a cell-type specific 3D genome modulator, which operates both independently and in cooperation with CTCF to set up the chromatin landscape of pyramidal neurons for cognitive processes. Overall design: To explore a role of SATB2 in shaping 3D epigenome, cultured cortical neurons derived from Satb2flx/flx::Nes-Cre (cKO) and Satb2flx/flx (floxed) mice were used. On DIV14, Satb2 cKO and floxed cultures were treated with bicuculline, a GABA-A receptor antagonist, which stabilizes/increased neuronal activity in all neurons. To identify changes in chromatin accessibility and chromatin interactions, three ATAC-seq and six Hi-C libraries were prepared per genotype, respectively. To map SATB2 binding sites genome-wide, two CUT&RUN libraries were prepared from floxed cultures.