Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report thatPOU3F2regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes,TRIM8(Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 inducesTRIM8expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region ofTRIM8. We investigated the cellular functions ofPOU3F2andTRIM8as they co-regulate several pathways related to neural development and synaptic function. Knocking down eitherPOU3F2orTRIM8promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate thatPOU3F2regulatesTRIM8expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.