| First Author | Chen R | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 9 | Pages | eabm1077 |
| PubMed ID | 35245111 | Mgi Jnum | J:328716 |
| Mgi Id | MGI:7256049 | Doi | 10.1126/sciadv.abm1077 |
| Citation | Chen R, et al. (2022) Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis. Sci Adv 8(9):eabm1077 |
| abstractText | 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. |
