Abstract：
The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of post-transcriptional mechanisms, however, the role of the latter underlying many diseases remains relatively unknown. By utilizing an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ), and controls, we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic changes of expression in neuropsychiatric disorders. Around 30% of the variability in expression can be attributed to post-transcriptional dysregulation. Interestingly, RNA stability tended to decrease in SCZ and BD, leading to the inhibition of neurogenesis and neural differentiation, while the increase in ASD, resulted in enhanced activity of apoptosis. This finding implicated contrasting pathologies involving RNA stability among neuropsychiatric disorders. An RNA binding protein (RBP)-ELAVL3 - is predicted to be significantly involved in the disruption of RNA stability in all three disorders. To validate, we knocked down its expression in cerebral organoids. Not only differentially expressed genes in ELAVL3-knockdown covered a considerable proportion of predicted targets in three disorders, we also found neurogenesis was significantly affected, given the diminished proliferation and consequently the reduced size of the organoids. Our study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new therapeutic targets for early intervention.
摘要：
基因表达的改变不仅限于转录调控，还包括多种转录后机制。然而,后者在许多疾病中的作用仍然相对未知。通过利用来自自闭症谱系障碍（ASD）个体的1510个大脑样本的RNA-Seq数据集，双相情感障碍（BD），精神分裂症（SCZ），和控制，我们评估了转录后失调的影响,并确定了神经精神疾病中转录组表达变化的主要扰动因子.约30%的表达变异性可归因于转录后失调。有趣的是,RNA稳定性在SCZ和BD中趋于下降，导致神经发生和神经分化的抑制，而ASD的增加，导致细胞凋亡活性增强。这一发现涉及神经精神疾病中涉及RNA稳定性的对比病理。预测RNA结合蛋白(RBP)-ELAVL3-在所有三种病症中显著参与RNA稳定性的破坏。要验证，我们下调了它在大脑类器官中的表达。不仅ELAVL3敲低中的差异表达基因覆盖了三种疾病中相当大比例的预测靶标，我们还发现神经发生受到显著影响，鉴于增殖减少，因此类器官的大小减小。我们的研究扩展了目前对转录后调控与神经精神疾病之间联系的理解，并为早期干预提供了新的治疗靶点。
