SATB2 organizes the 3D genome architecture of cognition in cortical neurons

SATB2 is genetically associated with human intelligence. Since SATB2 protein structure predicts a function in DNA looping, we analyzed the impact of SATB2 on 3D genome architecture and chromatin accessibility in cortical neurons. Our data reveal strong effects of SATB2 on chromatin looping between enhancers and promoters of neuronal activity-regulated genes, which closely correlate with gene expression. We furthermore identify SATB2-dependent alterations at all 3D genome architectural levels, including compartments, Topologically Associated 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. The altered non-coding regions are enriched for common variants associated with educational attainment, intelligence and schizophrenia. Our data establish SATB2 as a 3D genome organizer, which operates both independently and in cooperation with CTCF to set up the chromatin landscape of pyramidal neurons for cognitive processes.