The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.
The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.
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DOI：
10.1016/j.bbi.2023.06.009
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发表时间：
2023-08
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影响因子：
--
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长链非编码RNA（lncRNA）在调节脑基因网络中发挥着多方面的作用。LncRNA异常被认为是许多神经精神障碍的复杂病因学的基础。一个例子是人类lncRNA基因GOMAFU，它在精神分裂症（SCZ）死后大脑中发现失调，并含有导致SCZ风险的遗传变异。然而，GOMAFU调控的转录组范围的生物学途径尚未确定。GOMAFU调节异常如何导致SCZ发病机制仍不清楚。在这里，我们报告说，GOMAFU是一种新的抑制剂的人神经元干扰素（IFN）的反应途径是过度活跃的死后SCZ的大脑。我们分析了最近发布的来自多个SCZ队列的临床相关脑区的转录组学分析数据集，发现了GOMAFU的脑区特异性失调。使用CRISPR-Cas9删除人神经祖细胞模型中的GOMAFU启动子，我们在SCZ和自闭症谱系障碍（ASD）的死后大脑中通常受影响的通路中鉴定了由GOMAFU缺乏引起的转录组学改变，其中对IFN信号传导的许多基因的上调具有最显著的影响。此外，GOMAFU靶基因在IFN途径中的表达水平在SCZ脑区受到不同影响，并与GOMAFU改变呈负相关。此外，急性暴露于IFN-γ导致GOMAFU快速下降，并激活SCZ脑中受影响的应激和免疫反应途径中的GOMAFU靶点亚类，这形成了一个高度相互作用的分子网络。总之，我们的研究揭示了第一个证据的lncRNA控制的神经元反应途径干扰素的挑战，并表明GOMAFU失调可能介导的环境风险，并有助于神经精神疾病的脑神经元的病因神经炎症反应。
Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.
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影响因子：
4.3
作者：
Aliperti V;Skonieczna J;Cerase A
通讯作者：
Cerase A
影响因子：
8
作者：
Califano D;Furuya Y;Roberts S;Avram D;McKenzie ANJ;Metzger DW
通讯作者：
Metzger DW
影响因子：
11
作者：
Brennand, K. J.;Simone, A.;Tran, N.;Gage, F. H.
通讯作者：
Gage, F. H.
DOI：
10.1016/j.bbi.2022.06.010
发表时间：
2022-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
通讯作者：
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自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.