Brain transcriptome profiling in wildtype mice and mice with Igf2 enhancer deletion (Igf2enh-/-) [RNA-seq]

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. We report the first multi-omics study of neurons isolated from the prefrontal cortex of individuals with schizophrenia and bipolar disorder, including genome-wide neuronal DNA methylation using Illumina EPIC microarrays, transcriptomes and SNP genotypes (n=55 cases and 27 controls). Epigenetic, transcriptomic, and genetic-epigenetic interactions in disease converged on pathways of neurodevelopment, synaptic activity, and immune functions. Notably, we discovered prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in neurons of major psychosis patients. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene, which is responsible for dopamine synthesis. IGF2 enhancer hypomethylation was associated with increased TH protein levels in the human brain. The Igf2 enhancer was deleted in mice to explore the transcriptomic and proteomic consequences of this genomic locus in the frontal cortex and striatum. In mice, Igf2 enhancer deletion disrupted levels of TH protein and striatal dopamine, as well as induced transcriptional and proteomic abnormalities affecting development and synaptic function. Epigenetic control of the IGF2 enhancer may regulate dopamine levels and contribute to psychosis risk. We profiled transcriptomes from the frontal cortex and striatum of wild-type (N=14) and Igf2enh-/- (N=13) mice神经元功能受损（包括多巴胺失衡）是重型精神病发病的核心病理机制，但其具体分子起源尚不明确。本研究首次针对精神分裂症与双相情感障碍患者前额叶皮层分离得到的神经元开展多组学研究，检测内容包括基于Illumina EPIC微阵列的全基因组神经元DNA甲基化、转录组以及单核苷酸多态性（SNP）基因型（病例组55例，对照组27例）。疾病相关的表观遗传、转录组以及遗传-表观遗传互作均富集于神经发育、突触活动与免疫功能通路。值得注意的是，本研究在重型精神病患者的神经元中发现了胰岛素样生长因子2 (IGF2) 基因内增强子的显著低甲基化。染色质构象分析显示，该增强子靶向邻近的酪氨酸羟化酶 (TH) 基因，该基因负责多巴胺的合成。IGF2增强子低甲基化与人脑内TH蛋白水平升高相关。本研究在小鼠中敲除Igf2增强子，以探究该基因组位点在额叶皮层与纹状体中的转录组及蛋白质组学效应。在小鼠体内，Igf2增强子敲除会破坏TH蛋白与纹状体多巴胺的水平，并引发影响发育与突触功能的转录组及蛋白质组异常。IGF2增强子的表观遗传调控或可调节多巴胺水平，并参与精神病发病风险的形成。本研究对野生型（N=14）与Igf2enh-/-（N=13）小鼠的额叶皮层及纹状体转录组进行了表征分析。