Chen Renchao, Liu Yiqiong, Djekidel Mohamed N, Chen Wenqiang, Bhattacherjee Aritra, Chen Zhiyuan, Scolnick Ed, Zhang Yi
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Sci Adv. 2022 Mar 4;8(9):eabm1077. doi: 10.1126/sciadv.abm1077.
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 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.
精神分裂症（SCZ）是一种慢性、严重的精神障碍。尽管已经鉴定出200多个与SCZ相关的基因，但其潜在的分子和细胞机制在很大程度上仍不清楚。在这里，我们构建了一个Setd1a（含SET结构域蛋白1A）单倍体不足小鼠模型，以了解这种与SCZ相关的表观遗传因子如何影响与SCZ高度相关的脑区中的基因表达。单细胞RNA测序显示，Setd1a杂合性导致前额叶皮质（PFC）和纹状体中不同细胞类型之间的转录适应性高度可变。在PFC的不同神经元亚型中，神经元表现出最显著的基因表达变化，这与组蛋白H3赖氨酸4三甲基化的变化相关。Setd1a小鼠中失调的许多基因都参与神经元形态发生和突触功能。一致地，Setd1a小鼠表现出SCZ患者的某些行为特征。总的来说，我们的研究将Setd1a小鼠确立为理解SCZ的模型，并揭示了一种复杂的脑区和细胞类型特异性失调，这可能是SCZ发病机制的基础。
