Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability

During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population. Author summary SATB2 is a homeodomain protein that recruits transcriptional and epigenetic regulators to its DNA binding sites. We have recently shown that deletion of Satb2 from the forebrain of adult mice leads to impaired long-term memory. Human patients with SATB2 haploinsufficiency suffer from severe neurological symptoms including cognitive deficits, developmental delay and absent/limited speech. Here, we tested the hypothesis that SATB2 molecular functions differ between developing and adult cortex. Our results provide experimental support for this concept by demonstrating that 1) SATB2 interacts with different protein networks at the two ontogenetic stages, with a switch from transcriptional repression towards organization of chromatin structure and 2) SATB2 determines differential transcriptional programs in neonatal vs adult cortex. To explore the contribution of SATB2 interactomes to human cognition, we tested the sets of genes encoding SATB2 interactors for enrichment using the largest available genome-wide association studies (GWAS) datasets for cognitive ability and neuropsychiatric diseases. We found that genes encoding SATB2 interactomes are highly constrained. Rare high impact mutations in these genes cause severe cognitive disorders whereas common low impact variants influence general cognitive ability in the population. Given that SATB2 is a known 3D-genome organizer protein, our data emphasize the role of long-range chromatin interactions in human cognition and present novel and unsuspected candidates for further studies on the underpinnings of intelligence and the mechanisms underlying intelligence differences.