Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [bulk RNA-seq]

Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients' families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis. Bulk RNA-seq samples were generated from the PFC in WT and Setd+/- to study the global transcriptional changes induced by Setd1 loss. Fox2p+ PFC were FACS sorted and their transcriptome sequenced.精神分裂症（Schizophrenia, SCZ）是一种慢性重症精神障碍，给患者家庭与社会带来沉重负担。尽管已有超过100个基因被证实与精神分裂症的发病机制相关，但其潜在的分子与细胞机制仍未得到充分阐明。 本研究构建了Setd1a单倍剂量不足（haploinsufficiency）小鼠模型，以探究这一与精神分裂症相关的表观遗传因子，如何影响与精神分裂症高度相关的脑区细胞内的基因表达程序。 通过对比野生型（wild type）与Setd1a+/-小鼠的单细胞RNA测序（single-cell RNA-seq）结果，本研究发现Setd1a杂合性会导致前额叶皮层（prefrontal cortex，简称PFC）与纹状体（striatum）中不同细胞类型出现高度多样的转录适应现象，提示脑区与细胞类型特异性机制参与了精神分裂症的病理生理过程。 有趣的是，本研究发现PFC内不同神经元亚型中，Foxp2阳性神经元的基因表达变化最为显著，且该变化与组蛋白H3赖氨酸4三甲基化（H3K4me3）修饰改变相关。 尤为重要的是，Setd1a杂合小鼠中失调的诸多基因，均与神经元形态发生及突触功能密切相关。 一致的是，Setd1a杂合小鼠表现出精神分裂症患者的部分行为特征。 综上，本研究确立了Setd1a杂合小鼠作为精神分裂症研究的动物模型，并揭示了一组潜在参与精神分裂症发病机制的、复杂的脑区与细胞类型特异性表达变化。 本研究还从野生型（WT）与Setd1a+/-小鼠的PFC中获取批量RNA测序（bulk RNA-seq）样本，以探究Setd1a缺失诱导的全基因组转录变化。 研究人员通过荧光激活细胞分选（fluorescence-activated cell sorting，简称FACS）分离出PFC内的Foxp2阳性神经元，并对其转录组进行了测序。