SATB2, encoding a DNA-binding nuclear protein, is genetically associated with human intelligence and schizophrenia. Individuals with SATB2 haploinsufficiency suffer from SATB2-associated syndrome defined by developmental delay, severe intellectual disability, and absent/limited speech. In a previous study we have identified epigenetic profiles and higher-order chromatin interactions that depend on SATB2 in cortical pyramidal neurons of the mouse by integrating high-resolution, multidimensional datasets from Satb2 conditional knockout (cKO) and floxed mice. With remarkable specificity, SATB2-mediated 3D epigenome modelling occured at mouse genomic loci that are functionally associated with cognition. Here, we study the effect of SATB2 in human forebrain glutamatergic neurons, differentiated from induced pluripotent stem cell (hiPSC)-derived neural progenitors by Neurogenin 2 (NGN2) overexpression. In our model glutamatergic NGN2 neurons expressing recombinant SATB2 are compared to SATB2-negative control NGN2 neurons. As observed previously in mouse neurons, transcriptome profiling of human neurons reveals enrichment for synapse, behavior and membrane potential-related GO categories among the differentialy expressed genes between SATB2+ and SATB2- excitatory neurons. Currently, we are mapping SATB2 binding sites, SATB2-dependent chromatin accessibility and chromatin interaction changes in human neurons, which will be further compared to the corresponding sets derived from mouse primary cortical neurons. These analyses will uncover evolutionary observed as well as human-specific SATB2 effects on 3D epigenome and provide novel insights into gene regulatory mechanisms associated with human intelligence and neuropsychiatric disease.