biostudies-literatureWahl NIrish Research CouncilAustrian Science Fund FWFNIMH NIH HHSNational Institutes of Health621-639.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC10923151biostudies-literatureUnknown84(4)The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (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 a 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 CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.Molecular cellSATB2 organizes the 3D genome architecture of cognition in cortical neurons.PMC10923151R01MH117790FWF-P32850-BFWF-P33027-BR01 MH117790P 32850RCS1730FWF-DK W1206Wahl NEspeso-Gil SMorris DWDechant GLaighneach AApostolova GNagel AChietera PAkbarian SRajarajan PfalseSATB2 organizes the 3D genome architecture of cognition in cortical neurons.The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (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 a 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 CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.2024-01-01T00:00:00Z2024 Feb2026-06-03T04:49:04.303Z2025-07-11T03:04:07.402ZS-EPMC109231513824454510.1016/j.molcel.2023.12.024