Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ. Single-cell RNA sequencing revealed that Setd1a heterozygosity causes highly variable transcriptional adaptations across different cell types in prefrontal cortex (PFC) and striatum. The Foxp2(+) neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with changes in histone H3 lysine 4 trimethylation. Many of the genes dysregulated in Setd1a(+/-) mice are involved in neuron morphogenesis and synaptic function. Consistently, Setd1a(+/-) mice exhibit certain behavioral features of patients with SCZ. Collectively, our study establishes Setd1a(+/-) mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific dysregulation that potentially underlies SCZ pathogenesis.

Automated summary

In this study, a Setd1a haploinsufficiency mouse model was generated to investigate the effect of this SCZ-associated epigenetic factor on gene expression in brain regions relevant to SCZ. The results showed that Setd1a heterozygosity leads to highly variable transcriptional adaptations in different cell types in the prefrontal cortex and striatum, and the Foxp2(+) neurons exhibit the most prominent gene expression changes. Additionally, Setd1a(+/-) mice display behavioral features similar to SCZ patients, suggesting a potential role of Setd1a in SCZ pathogenesis.