LncRNA调控神经炎症参与精神分裂症发病的表观遗传调控机制研究

Epigenetic modification play a seminal role in mediating the interplay between genetics and environmental factors underlying the development of schizophrenia (SZ). Environmental factors such as prenatal infections, by virtue of activating the epigenetic changes or systemic inflammation, disrupt normal gene expression or development of the central nervous system, which then trigger susceptibility to disease. However, the underlying mechanism need to be examined...Based on our preliminary data that functional pathway of SZ-related lncRNA-mRNAs is enriched in inflammation pathway, the current proposal hypothesizes lncRNA-regulated neuroinflammation underlying the development of SZ. This proposed study will perform transcriptome analysis of RNA from monozygotic (MZ) twin pairs that are discordant or concordant for SZ, as well as healthy twin pairs. The study will systematic profile genome-wide differential expressions of lncRNAs and mRNAs, as well as co-expressed lncRNA-mRNAs and functional pathway involved in neuroinflammation. The regulatory molecular and cellular mechanisms of functional co-expressed lncRNA-mRNAs involved in neuroinflammation, will be evaluated in a neuroblast-like SH-5Y5Y cell line, an animal behavioral model, human iPSC-derived microglia-like cells (hiMLCs), 2-D cortical neurons or 3-D forebrain organoids from MZ twins, and blood RNA of unrelated disease cases and controls...This study will contribute greatly to our understanding of lncRNA-regulated neuroinflammation underlying individual differences in the phenotype and disease susceptibility of MZ-twin pairs and provide strong evidence for new biological markers that may exploited for motoring the development of SZ.

表观遗传学修饰作为介导遗传与环境因素互作的重要机制，在精神分裂症（SZ）发生发展中起着重要作用。环境因素如胚胎期感染可引发炎症或表观遗传修饰变化，造成基因表达和神经系统发育异常而增加患病风险，但具体机制有待阐明。针对我们前期发现长链非编码RNA(lncRNA)的靶基因显著富集于炎症通路，本项目提出lncRNA调控神经炎症参与SZ发生发展的假说，并以同卵双生子对异患和同患SZ、健康双生子对为研究对象，开展转录组检测和分析，系统绘制SZ相关lncRNA-mRNA共表达网络图谱及调控神经炎症相关通路基因簇；利用SH-5Y5Y细胞株,小鼠动物行为模型,双生子来源的iPSCs及其分化的小胶质细胞、皮层神经元及前脑类器官和散发病例-对照样本，研究lncRNA调控神经炎症通路参与SZ发生发展的细胞和分子调控机制及其对SZ表型变异影响的普遍性规律，为探索监测SZ发生发展的新型在体生物标记提供新的科学证据。

精神分裂症（SZ）是一种复杂的多基因疾病，受遗传、发育和环境因素的影响。越来越多的证据表明，母体感染和过度的产前神经炎症等环境因素可能通过影响表观遗传修饰来促进精神分裂症的发生。本项目以SZ单发病同卵双生子对以及健康同卵双生子对的外周血RNA开展RNA-seq和分析，筛选到两个SZ相关的上调lncRNA AC006129.1和RP5-998N21.4。它们在尸检脑组织RNA-seq数据集中以及独立血液RNA队列的qPCR分析结果中均显示出一致的表达上调。我们发现这两个lncRNAs共表达的基因显著富集于免疫防御相关功能通路，表明了他们在SZ的发病机制中具有功能意义。接下来，我们发现AC006129.1在SZ中通过增强SOCS3和CASP1的表达参与炎症反应，并在表现出SZ相关异常行为的AC006129.1过表达小鼠中进一步验证了这一发现；AC006129.1结合到转录抑制因子Capicua (CIC)的启动子区域，促进DNMTs与CIC启动子的相互作用介导CIC的下调，从而解除CIC对SOCS3和CASP1抑制。SOCS3的解除抑制通过抑制JAK/STAT信号的激活来增强抗炎反应。我们通过整合分析RP5-998N21.4 过表达SK-N-SH细胞中的DEGs和来自双胞胎RP5-998N21.4共表达的SZ相关DEGs，发现免疫防御中发挥重要作用的IFIT2和IFIT3基因为RP5-998N21.4的潜在靶点。进一步证明RP5-998N21.4通过结合这两个基因启动子区域并影响其组蛋白修饰，正向调控其转录活性。我们鉴定出一种通用核共激活子RMB14为促进RP5-998N21.4在IFIT2和IFIT3转录中的调节作用。最后，我们观察到RP5-998N21.4OE可以通过激活病毒模拟poly I:C处理U251细胞的STAT1信号通路，增强IFIT2和IFIT3介导的免疫防御反应。综上所述，我们的研究结果表明，lncRNAs AC006129.1和RP5-998N21.4是免疫防御的重要调节因子，在SZ的病因学和治疗方面具有重要意义。相关成果发表在2021 Molecular Psychiatry，2022和2021年Schizophrenia和2022 Frontiers in Genetics 杂志，培养4名博士研究生和3名硕士研究生毕业。